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Aims: Previous studies have shown that proteinuria is independently associated with the incidence of atrial fibrillation (AF), and is also associated with the incidence of cardiovascular events such as stroke and thromboembolism in patients with AF. However, the association of proteinuria with heart failure (HF) events in patients with AF remains unclear., Methods and Results: The Fushimi AF Registry is a community-based prospective study of patients with AF. Of the entire cohort of 4489 patients, 2164 patients had available data of proteinuria. We compared the clinical background and outcomes between patients with proteinuria (n = 606, 28.0%) and those without (n = 1558, 72.0%). Patients with proteinuria were older and had a higher prevalence of major co-morbidities. During the median follow-up of 5.0 years, the incidence rates of HF events (composite of cardiac death or HF hospitalization) were higher in patients with proteinuria than those without (4.1% vs. 2.1% person-year, P < 0.01). Multivariate analyses revealed that proteinuria was an independent risk factor of the incidence of HF events [adjusted hazard ratio (HR): 1.40, 95% confidence interval (CI): 1.13-1.74]. This association was consistent among the various subgroups, except for the age subgroup in which there was a significant interaction (P < 0.01) between younger (<75 years) (unadjusted HR: 3.03, 95% CI: 2.12-4.34) and older (≥75 years) patients (unadjusted HR: 1.59, 95% CI: 1.23-2.05)., Conclusion: Our community-based large prospective cohort suggests that proteinuria is independently associated with the incidence of HF events in Japanese patients with AF., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Citrus depressa Hayata is a small-fruit citrus species; it is indigenous to Kagoshima, Okinawa, and Taiwan. The metabolites and volatile organic compounds (VOCs) that affect the flavor of its fruits have not been investigated based on geographical origin. In the present study, we investigated the metabolite and VOC profiles of 18 C. depressa cultivation lines from these regions. Multivariate analysis revealed differences in the metabolites of C. depressa based on its cultivation origins; variations in sugar, sugar alcohol, and amino acid contents were also observed. Fruits from Kagoshima and Okinawa had higher galactinol, trehalose, xylose, glucose, and sucrose intensities than fruits from Taiwan (log 2 -fold change; 2.65-3.44, 1.68-2.13, 1.37-2.01, 1.33-1.57, and 1.07-1.43, respectively), whereas the Taiwanese lines contained higher leucine, isoleucine, serine, and alanine. In contrast to the Taiwanese Nantou line, other cultivation lines had comparable total VOC contents, and the VOCs of all lines were dominated by limonene, γ -terpinene, and p -cymene. Accordingly, the highest VOC intensities were recorded in the Nantou line, which was followed by Shikunin sweet (Kagoshima) and Taoyuan (Taiwan) (log 10 normalize concentration; 5.11, 3.08, and 3.01, respectively). Moreover, multivariate analysis plots elucidated the difference in the VOCs of Ishikunibu (Okinawa), Shikunin sweet, and Taoyuan and between those of most Kagoshima and Okinawa cultivation lines. These results suggest that both the cultivation line and origin influence the metabolites and VOCs of C. depressa , thus possibly affecting its flavor quality; the data provide a valuable insight for utilizing C. depressa of different cultivation lines and origins to produce foods and beverages.

Background: Mycobacterium avium complex (MAC) causes chronic respiratory infectious diseases with diverse clinical features and prognoses. Pleuroparenchymal fibroelastosis (PPFE) is a rare disease characterised by pleural fibrosis with subjacent intra-alveolar fibrosis and alveolar septal elastosis, with unique chest high-resolution CT (HRCT) features (radiological PPFE). An association between recurrent respiratory infections and PPFE formation has been hypothesised; however, the clinical significance of PPFE in MAC lung disease remains unclear., Methods: This retrospective, multicentre study investigated the prevalence of radiological PPFE in patients with MAC lung disease and its association with clinical features and outcomes. Radiological PPFE was diagnosed on the basis of HRCT findings. Prognostic factors were identified using Cox proportional hazards and Fine-Gray models., Results: Of 850 consecutive patients with definite MAC lung disease, 101 (11.9%) exhibited radiological PPFE. Patients with radiological PPFE had unique characteristics, such as lower body mass index, lower survival rate (5-year cumulative survival rate, 63.1% vs 91.7%; p<0.001) and a higher incidence of respiratory-related death (5-year cumulative incidence, 31.1% vs 3.6%; p<0.001), than those without radiological PPFE. In the multivariable analysis, the presence of radiological PPFE was independently associated with all-cause mortality (adjusted HR, 4.78; 95% CI, 2.87 to 7.95; p<0.001) and respiratory-related death (adjusted HR, 3.88; 95% CI, 2.14 to 7.01; p<0.001)., Interpretation: This large-scale study demonstrated that in patients with MAC lung disease, radiological PPFE was common, a phenotype associated with unique clinical features and poor prognosis, particularly respiratory-related death. The specific management of this subgroup should be established., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Documentary climate data describe evidence of past climate arising from predominantly written historical documents such as diaries, chronicles, newspapers, or logbooks. Over the past decades, historians and climatologists have generated numerous document-based time series of local and regional climates. However, a global dataset of documentary climate time series has never been compiled, and documentary data are rarely used in large-scale climate reconstructions. Here, we present the first global multi-variable collection of documentary climate records. The dataset DOCU-CLIM comprises 621 time series (both published and hitherto unpublished) providing information on historical variations in temperature, precipitation, and wind regime. The series are evaluated by formulating proxy forward models (i.e., predicting the documentary observations from climate fields) in an overlapping period. Results show strong correlations, particularly for the temperature-sensitive series. Correlations are somewhat lower for precipitation-sensitive series. Overall, we ascribe considerable potential to documentary records as climate data, especially in regions and seasons not well represented by early instrumental data and palaeoclimate proxies., (© 2023. The Author(s).)

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. The pathogenesis of ALS remains largely unknown; however, inflammation of the spinal cord is a focus of ALS research and an important pathogenic process in ALS. Prostaglandin E 2 (PGE 2 ) is a major lipid mediator generated by the arachidonic-acid cascade and is abundant at inflammatory sites. PGE 2 levels are increased in the postmortem spinal cords of ALS patients and in ALS model mice. Beneficial therapeutic effects have been obtained in ALS model mice using cyclooxygenase-2 inhibitors to inhibit the biosynthesis of PGE 2 , but the usefulness of this inhibitor has not yet been proven in clinical trials. In this review, we present current evidence on the involvement of PGE 2 in the progression of ALS and discuss the potential of microsomal prostaglandin E synthase (mPGES) and the prostaglandin receptor E-prostanoid (EP) 2 as therapeutic targets for ALS. Signaling pathways involving prostaglandin receptors mediate toxic effects in the central nervous system. In some situations, however, the receptors mediate neuroprotective effects. Our recent studies demonstrated that levels of mPGES-1, which catalyzes the final step of PGE 2 biosynthesis, are increased at the early-symptomatic stage in the spinal cords of transgenic ALS model mice carrying the G93A variant of superoxide dismutase-1. In addition, in an experimental motor-neuron model used in studies of ALS, PGE 2 induces the production of reactive oxygen species and subsequent caspase-3-dependent cytotoxicity through activation of the EP2 receptor. Moreover, this PGE 2 -induced EP2 up-regulation in motor neurons plays a role in the death of motor neurons in ALS model mice. Further understanding of the pathophysiological role of PGE 2 in neurodegeneration may provide new insights to guide the development of novel therapies for ALS., (© 2023. The Author(s).)

Objectives: The detailed pathological mechanism of orofacial neuropathic pain remains unknown. We aimed to examine the pannexin 1 (Panx1) signaling in the trigeminal ganglion (TG) involvement in infraorbital nerve injury (IONI)-induced orofacial neuropathic pain., Materials and Methods: Mechanical head-withdrawal threshold (MHWT) was measured in IONI-treated rats receiving intra-TG Panx1 inhibitor or metabotropic glutamate receptor 5 (mGluR5) antagonist administration and MHWTs in naive rats receiving intra-TG mGluR5 agonist administration post-IONI. Glutamate and Panx1 in the TG were measured post-IONI. Panx1, mGluR5, and glutamine synthetase expression in TG were immunohistochemically identified, and changes in the number of mGluR5-P2X 3 -expressed TG neurons were examined., Results: MHWT was significantly decreased post-IONI, and this decrease was reversed by Panx1 inhibition or mGluR5 antagonism. mGluR5 agonism induced a decrease in the MHWT. IONI increased extracellular glutamate in TG. Panx1 was expressed in satellite glial cells and TG neurons, and intra-TG mGluR5 antagonism decreased the number of mGluR5 and P2X 3 positive TG neurons post-IONI., Conclusions: IONI facilitates glutamate release via Panx1 that activates mGluR5 which was expressed in the nociceptive TG neurons innervating the orofacial region. In turn, P2X 3 receptor-expressed TG neurons are enhanced via mGluR5 signaling, resulting in orofacial neuropathic pain., (© 2022 Wiley Periodicals LLC.)

Nandrolone, an anabolic androgenic steroid, is included in the prohibited list of the World Anti-Doping Agency. Drugs of abuse activate brain dopamine neurons and nandrolone has been suspected of inducing dependence. Accordingly, possible critical periods for the effects of nandrolone on muscular strength and dopaminergic activity have been investigated, including the effects of chronically administered nandrolone alone and on morphine-induced increases in dopamine efflux in the nucleus accumbens. Six- or 10-week-old male Sprague-Dawley rats were used. Treatment with nandrolone was initiated in adolescent (6-week-old) and young adult (10-week-old) rats. Nandrolone (5.0 mg/kg s.c.) or sesame oil vehicle was given once daily, on six consecutive days per week, for 3 weeks and then once per day for 4 consecutive days. Nandrolone enhanced the developmental increase in grip strength of 6- but not 10-week-old rats, without altering the developmental increase in body weight of either age group. Using in vivo microdialysis in freely moving 6-week-old rats given nandrolone for 4 weeks, basal accumbal dopamine efflux was unaltered, while the increase in dopamine efflux induced by acute administration of morphine (1.0 mg/kg s.c.) was reduced. The present study provides in vivo evidence that adolescence constitutes a critical period during which repeated administration of nandrolone enhances increases in muscular strength without influencing increases in body weight. Though repeated administration of nandrolone during this period of adolescence did not stimulate in vivo mesolimbic dopaminergic activity, it disrupted stimulation by an opioid, the drug class that is most commonly coabused with nandrolone., (© 2023 Wiley Periodicals LLC.)

The present study aimed to investigate the factors affecting the cardiac uptake of 18F-fluorodeoxyglucose (18F-FDG) during 18F-FDG positron emission tomography (PET) for new-onset rectal cancer and new-onset colon cancer (ascending, transverse, descending, sigmoid colon cancer) and to examine the association between the cardiac uptake of 18F-FDG and prognosis. The participants were diagnosed with new-onset rectal cancer and new-onset colon cancer (ascending, transverse, descending, sigmoid cancer) at the Iga City General Hospital (Iga, Japan) between January 1, 2013, and March 31, 2018, and underwent an 18F-FDG PET scan for pretreatment staging. The relationship between cardiac maximum standard uptake value (SUVmax), the presence/absence of distant metastasis and prognosis was examined. A total of 26 patients (14 men and 12 women) aged 72.0±10 years with new-onset rectal cancer were selected for the study. No patients had multiple simultaneous cancers. The median cardiac SUVmax was 3.8 and 2.5 in patients with no distant metastasis and distant metastasis, respectively, revealing a statistically significant difference (P<0.01). The median tumor volume on PET-computed tomography (CT) images was 7,815 cm 2 and was 66,248 cm 2 in patients with no distant metastasis and distant metastasis, respectively, revealing a statistically significant difference (P<0.01). Echocardiography findings revealed no significant difference between patients with and without distant metastasis. The correlation coefficient between cardiac SUVmax and total tumor volume on PET/CT images (primary + lymph + distant metastases) was statistically significant (r=-0.42, P=0.03). Analysis of the association between the occurrence of distance metastasis and cardiac SUVmax as a continuous variable gave a statistically significant result [hazard ratio (HR): 0.30, 95% confidence interval (CI): 0.09-0.98, P=0.045]. Receiver operating characteristic analysis showed a cardiac SUVmax of 2.6 with an area under the curve of 0.86 for determining the presence of distant metastasis (95% CI: 0.70-1.00). The median observation time was 56 months, and nine patients died during observation. Analysis of the association between the overall survival and cardiac SUVmax (cutoff: 2.6) showed 95% CI: 0.01-0.45 and HR: 0.06 (P<0.01); that between the overall survival and total tumor volume on PET images showed 95% CI: 1.00-1.00 and HR: 1.00 (P<0.01); and that between the overall survival and presence of distant metastasis showed 95% CI: 1.72-116.4 and HR: 14.1 (P<0.01). Furthermore, 25 patients (16 men and nine women) aged 71.4±14.2 years with new-onset colon cancer were selected for the study. Analysis of new-onset colon cancer revealed no statistically significance between the cardiac SUVmax and distant metastasis., Competing Interests: Iga City and the Iga City General Hospital have established endowed chairs with the Department of Gastroenterology and Hepatology at the Kansai Medical University and with the Departments of Gastroenterology and Pediatric Surgery at Mie University. This study was conducted as a research project with Department of Gastroenterology and Hepatology at the Kansai Medical University, Departments of Gastroenterology and Pediatric Surgery at Mie University, and Iga city General Hospital at Iga city General Hospital. YO received a lecture fee (not related this research) and is an officer of EIIS (Expert Imaging and Interventional Support) which charges for the imaging reading at Iga city General Hospital (no reward as an officer). However, the authors declare that they have no competing interests., (Copyright: © Sawaragi et al.)

Asthma is a chronic airway inflammatory disease characterized by airway hyperreactivity (AHR) and eosinophilic airway inflammation. Dendritic cells (DCs) are essential for the development of asthma via presenting allergens, causing T-helper cell type 2 (Th2) skewing and eosinophil inflammation. Recent studies have revealed that CD109, a glycosylphosphatidylinositol-anchored glycoprotein, is involved in the pathogenesis of inflammatory diseases such as rheumatoid arthritis and psoriasis. However, no study has addressed the role of CD109 in asthma. This study sought to address the role of CD109 on DCs in the development of AHR and allergic inflammation. CD109-deficient mice ( CD109 -/- ) were sensitized with house dust mite or ovalbumin and compared with wild-type mice for induction of AHR and allergic inflammation. CD109-deficient mice had reduced AHR and eosinophilic inflammation together with lower Th2 cytokine expression compared with wild-type mice. Interestingly, CD109 expression was induced in lung conventional DC2s (cDC2s), but not lung cDC1s, upon allergic challenge. Lung cDC2s from CD109 -/- mice had a poor ability to induce cytokine production in ex vivo DC-T cell cocultures with high expression of RUNX3 (runt-related transcription factor 3), resulting in suppression of Th2 differentiation. Adoptive transfer of bone marrow-derived CD109 -/- DCs loaded with house dust mite failed to develop AHR and eosinophilic inflammation. Finally, administration of monoclonal anti-CD109 antibody reduced airway eosinophils and significantly decreased AHR. Our results suggest the involvement of CD109 in asthma pathogenesis. CD109 is a novel therapeutic target for asthma.

Colorectal cancer is a significant cause of morbidity and represents a serious public health issue in many countries. The development of a breakthrough preventive method for colorectal cancer is urgently needed. Aspirin has recently been attracting attention as a cancer preventive drug, and its inhibitory effects on the development of various cancers have been reported in several large prospective studies. However, the underlying molecular mechanisms have not yet been elucidated in detail. In the present study, we attempted to identify the target proteins of aspirin using a chemical biology technique with salicylic acid, the main metabolite of aspirin. We generated salicylic acid-presenting FG beads and purified salicylic acid-binding proteins from human colorectal cancer HT-29 cells. The results obtained showed the potential of ribosomal protein S3 (RPS3) as one of the target proteins of salicylic acid. The depletion of RPS3 by siRNA reduced CDK4 expression and induced G1 phase arrest in human colorectal cancer cells. These results were consistent with the effects induced by the treatment with sodium salicylate, suggesting that salicylic acid negatively regulates the function of RPS3. Collectively, the present results show the potential of RPS3 as a novel target for salicylic acid in the protective effects of aspirin against colorectal cancer, thereby supporting RPS3 as a target molecule for cancer prevention., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Toshiyuki Sakai reports financial support was provided by Japan Society for the Promotion of Science., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Acute exacerbation (AE) of systemic autoimmune disease-related interstitial lung diseases (SAID-ILD) is less common than AE of idiopathic pulmonary fibrosis (IPF) and the details of AE-SAID-ILD have not been elucidated, but the prognosis is similarly devastating. This study was undertaken to determine the incidences of AE-ILD in each SAID and to elucidate the proportion of progressive fibrosing (PF)-ILD in AE-SAID-ILD., Methods: We retrospectively analysed data for patients with SAID-ILD who were diagnosed and observed at our hospital between 1999 and 2020., Results: Two hundred and thirty-two patients with SAID-ILD were enrolled, with a mean observation period of 100.2 months. AE-SAID-ILD was found in 25 patients (10.78%), mainly in patients with RA (17 patients, 68%) and elderly male patients with a smoking history. The overall incidence of AE-SAID-ILD was 1.29%/person-year, and the incidence for each SAID was as follows: RA 2.193, microscopic polyarteritis (MPA) 3.203, systemic sclerosis (SSc) 2.277, primary Sjögren syndrome 0.426, and polymyositis/dermatomyositis 0.222. The incidence of AE of RA/MPA/SSc-ILD was significantly higher than that of other AE-SAID-ILD (p < 0.001). Five of 25 patients (20%) fulfilled the criteria for PF-ILD. The 90-day survival rate was 48.0%, and a higher neutrophil count at AE (HR 13.27, 95%CI 2.447-246, p = 0.001) and early commencement of long-duration direct haemoperfusion with a polymyxin B-immobilised fibre column (HR 0.105, 95%CI 0.005-0.858, p = 0.035) were significant prognostic factors., Conclusions: The incidence of AE-SAID-ILD was significantly higher in patients with RA, MPA, or SSc than in patients with other SAID. Furthermore, even in patients with AE-SAID-ILD, the proportion of PF-ILD just before AE was not high (20%)., (© 2022. The Author(s).)

Obesity is a common comorbidity in patients with asthma, and obese asthma patients present the most refractory phenotype among patients with severe asthma. Similar to the observations in non-obese asthma patients, clinical studies have revealed heterogeneity in obese asthma patients, including the occurrences of T helper (Th)2-high and Th2-low phenotypes. However, the mechanisms underlying obesity-related asthma are not completely understood. Though macroautophagy/autophagy is involved in asthma and obesity, its role in obesity-associated asthma is unknown. We hypothesized that autophagy is involved in the pathogenesis of obese asthma. For our investigations, we used high-fat diet-induced Atg5 (autophagy related 5)-deficient mice and epithelial cell-specific atg5 -/- ( Scgb1a1/CCSP-atg5 -/- ) obesity-induced mice. House dust mite (HDM)-sensitized atg5 -/- obese mice exhibited marked eosinophilic inflammation and airway hyper-reactivity (AHR), compared to wild-type (WT) obese mice. Analyses of atg5 -/- obese mice showed increased levels of Th2 cells but not ILC2s together with elevated expression of Th2 cytokines in the lung. In response to the HDM challenge, activated epithelial autophagy was observed in lean but not obese WT mice. Epithelium-specific deletion of Atg5 induced eosinophilic inflammation in Scgb1a1/CCSP-atg5 -/- obese mice, and genetic analyses of epithelial cells from HDM-immunized atg5 -/- obesity-induced mice showed an elevated expression of thymic stromal lymphopoietin (TSLP) and IL33. Notably, HDM-sensitized atg5 -/- mice developed TSLP- and IL33-dependent eosinophilic inflammation and AHR. Our results suggest that autophagy contributes to the exacerbation of eosinophilic inflammation in obese asthma. Modulations of autophagy may be a therapeutic target in obesity-associated asthma. Abbreviations: AHR: airway hyper-reactivity; BAL: bronchoalveolar lavage; C dyn : dynamic compliance; BM: bone marrow; HDM: house dust mite; HFD: high-fat diet; ILC2s: type 2 innate lymphocyte cells; ROS: reactive oxygen species; R L : lung resistance; TSLP: thymic stromal lymphopoietin; TCC: total cell count; WT: wild type.

Leaf senescence accompanied by yellowing and Rubisco degradation occurs prematurely in response to various stresses. However, signaling pathways between stress perception and senescence responses are not understood fully, although previous studies suggest the involvement of reactive oxygen species (ROS). While investigating the physiological functions of autophagy in Physcomitrium patens using wild-type (WT) and autophagy-deficient atg5 strains, we found that Physcomitrium colonies senesce prematurely under dark or nitrogen-deficient conditions, with atg5 senescing earlier than WT. In the present study, we measured cellular H2O2, and examined whether H2O2 mediates premature senescence in Physcomitrium colonies. Methyl viologen, an ROS generator, increased cellular H2O2 levels and caused senescence-like symptoms. H2O2 levels were also elevated to the same plateau levels in WT and atg5 under dark or nitrogen-deficient conditions. The ROS scavenger N-acetylcysteine and the ROS source inhibitor carbonyl cyanide m-chlorophenylhydrazone inhibited the increase in H2O2 levels as well as senescence. Upon transfer to a nitrogen-deficient medium, H2O2 levels increased earlier in atg5 than in WT by ~18 h, whereas atg5 yellowed earlier by >2 days. We conclude that the increased H2O2 levels under dark or nitrogen-deficient conditions mediate premature senescence in Physcomitrium but do not explain the different senescence responses of WT and atg5 cells.

The physiological implications of autophagy in plant cells have not been fully elucidated. Therefore, we investigated the consequences of autophagy in the moss Physcomitrella by measuring biochemical parameters (fresh and dry weights; starch, amino acid, carbohydrate, and NH3 content) in wild-type (WT) and autophagy-deficient atg5 Physcomitrella cells. We found higher starch levels and a higher net starch synthesis rate in WT cells than in atg5 cells cultured in a glucose-containing culture medium, whereas net starch degradation was similar in the two strains cultured in a glucose-deficient culture medium. Additionally, the treatment of cells with the autophagy inhibitor 3-methyladenine suppressed starch synthesis. Loading bovine serum albumin into atg5 cells through endocytosis, i.e., supplying proteins to vacuoles in the same way as through autophagy, accelerated starch synthesis, whereas loading glutamine through the plasma membrane had no such effect, suggesting that Physcomitrella cells distinguish between different amino acid supply pathways. After net starch synthesis, NH3 levels increased in WT cells, although the change in total amino acid content did not differ between WT and atg5 cells, indicating that autophagy-produced amino acids are oxidized rapidly. We conclude that autophagy promotes starch synthesis in Physcomitrella by supplying the energy obtained by oxidizing autophagy-produced amino acids.

Patients with idiopathic pulmonary fibrosis (IPF) are at a high risk of lung cancer (LC). Antifibrotic therapy slows disease progression and possibly prolongs survival. However, whether antifibrotic therapy affects LC development in patients with IPF remains unknown. This multicentre retrospective study evaluated 345 patients with IPF. The incidence and prevalence of LC were significantly lower in patients with IPF receiving antifibrotic therapy than those not receiving. Subsequently, LC-related mortality was significantly lower in patients with IPF receiving antifibrotic therapy. These results suggest that antifibrotic therapy was possibly associated with a reduced risk of LC development in patients with IPF, which may be partly associated with its survival benefit., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Cyclins and cyclin-dependent kinases (CDKs) regulate the cell cycle, which is important for cell proliferation and development. Cyclins bind to and activate CDKs, which then drive the cell cycle. The expression of cyclins periodically changes throughout the cell cycle, while that of CDKs remains constant. To elucidate the mechanisms underlying the constant expression of CDKs, we search for compounds that alter their expression and discover that the natural product fucoxanthinol downregulates CDK2, 4, and 6 expression. We then develop a method to immobilize a compound with a hydroxyl group onto FG beads ® and identify human ribosomal protein uS7 (also known as ribosomal protein S5) as the major fucoxanthinol-binding protein using the beads and mass spectrometry. The knockdown of uS7 induces G1 cell cycle arrest with the downregulation of CDK6 in colon cancer cells. CDK6, but not CDK2 or CDK4, is degraded by the depletion of uS7, and we furthermore find that uS7 directly binds to CDK6. Fucoxanthinol decreases uS7 at the protein level in colon cancer cells. By identifying the binding proteins of a natural product, the present study reveals that ribosomal protein uS7 may contribute to the constant expression of CDK6 via a direct interaction., (© 2022. The Author(s).)

We reconstructed April mean temperatures in Kyoto since the fifteenth century by investigating historical documents such as diaries and chronicles and compiling phenological data series of the full bloom date for herbaceous peony. In order to fill gaps in phenological data series, we used the full bloom date of rabbit-ear iris, an herbaceous plant that flowers at about the same time of the year as an herbaceous peony. We obtained floral phenological data covering a total of 278 years. Calibration using modern temperature data showed herbaceous peony phenology to be the preferred data source for April temperature estimation. Variations in the reconstructed April temperatures in Kyoto were synchronous with changes in the solar cycle. In particular, April temperatures were about 2 ℃ lower than at present around the ends of the Spoerer and Maunder grand solar minima, from 1550 to 1590 and from 1690 to 1730, respectively. In addition, the reconstructed April temperatures suggested a time lag in the climate response to solar activity changes that was about 10 years longer than the previously estimated lags in the responses of wintertime and March temperatures. However, further research is needed to accurately quantify this time lag., (© 2022. The Author(s) under exclusive licence to International Society of Biometeorology.)

The advancement of metabolomics in terms of techniques for measuring small molecules has enabled the rapid detection and quantification of numerous cellular metabolites. Metabolomic data provide new opportunities to gain a deeper understanding of plant metabolism that can improve the health of both plants and humans that consume them. Although major public repositories for general metabolomic data have been established, the community still has shortcomings related to data sharing, especially in terms of data reanalysis, reusability and reproducibility. To address these issues, we developed the RIKEN Plant Metabolome MetaDatabase (RIKEN PMM, http://metabobank.riken.jp/pmm/db/plantMetabolomics), which stores mass spectrometry-based (e.g. gas chromatography-MS-based) metabolite profiling data of plants together with their detailed, structured experimental metadata, including sampling and experimental procedures. Our metadata are described as Linked Open Data based on the Resource Description Framework using standardized and controlled vocabularies, such as the Metabolomics Standards Initiative Ontology, which are to be integrated with various life and biomedical science data using the World Wide Web. RIKEN PMM implements intuitive and interactive operations for plant metabolome data, including raw data (netCDF format), mass spectra (NIST MSP format) and metabolite annotations. The feature is suitable not only for biologists who are interested in metabolomic phenotypes, but also for researchers who would like to investigate life science in general through plant metabolomic approaches., (© The Author(s) 2021. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists.)

As colon cancer is one of the most common cancers in the world, practical prevention strategies for colon cancer are needed. Recently, treatment with aspirin and/or 5-aminosalicylic acid-related agents was reported to reduce the number of intestinal polyps in patients with familial adenomatous polyposis. To evaluate the mechanism of aspirin and 5-aminosalicylic acid for suppressing the colon polyp growth, single and combined effects of 5-aminosalicylic acid and sodium salicylate (metabolite of aspirin) were tested in the two human colon cancer cells with different cyclooxygenase-2 expression levels and intestinal polyp-derived cells from familial adenomatous polyposis model mouse. The combination induced cell-cycle arrest at the G1 phase along with inhibition of cell growth and colony-forming ability in these cells. The combination reduced cyclin D1 via proteasomal degradation and activated retinoblastoma protein. The combination inhibited the colony-forming ability of mouse colonic mucosa cells by about 50% and the colony-forming ability of mouse intestinal polyp-derived cells by about 90%. The expression level of cyclin D1 in colon mucosa cells was lower than that in intestinal polyp-derived cells. These results suggest that this combination may be more effective in inhibiting cell growth of intestinal polyps through cyclin D1 down-regulation., Competing Interests: No potential conflicts of interest were disclosed., (Copyright © 2022 JCBN.)

The nucleus accumbens contain orexinergic neural inputs and orexin OX 1 - and OX 2 -receptors. Behavioural studies suggest that accumbal orexin receptors modulate accumbal dopaminergic activity-dependent locomotion in rats. We studied the effects of intra-accumbal injection of orexin receptor ligands on accumbal extracellular dopamine levels in freely moving rats, using in vivo microdialysis and analysed the roles of OX 1 - and OX 2 -receptors in the regulation of basal accumbal dopamine efflux. The orexin receptor ligands were applied intra-accumbally though a microinjection needle attached with a dialysis probe. Neither the nonselective OX 1 - and OX 2 -receptor agonist orexin-A nor the preferential OX 2 -receptor agonist orexin-B (500.0 pg and 5.0 ng) altered accumbal dopamine levels. The nonselective OX 1 - and OX 2 -receptor antagonist MK-4305 (suvorexant, 500.0 pg, 2.5 and 5.0 ng) enhanced dopamine efflux. A 2-h tetrodotoxin infusion into nucleus accumbens through the probe or co-administration of orexin-A (500.0 pg) strongly inhibited MK-4305 (5.0 ng)-induced accumbal dopamine efflux. The selective OX 2 -receptor antagonist EMPA (90.0 and 900.0 pg, 9.0 ng) increased dopamine efflux. Intra-accumbal infusion of tetrodotoxin abolished EMPA (9.0 ng)-induced dopamine efflux. The selective OX 1 -receptor antagonist SB-334867 (10.0 and 20.0 ng) failed to alter dopamine efflux. Co-administration of orexin-B (500.0 pg) inhibited both EMPA (9.0 ng)- and MK-4305 (5.0 ng)-induced dopamine efflux. Intraperitoneal injection of MK-4305 (10.0 mg/kg) did not affect accumbal dopamine efflux. The present study provides in vivo neuropharmacological evidence that accumbal OX 2 - but not OX 1 -receptors exert inhibitory regulation of basal accumbal dopamine efflux and that blockade of accumbal OX 2 -receptors enhances dopamine efflux in nucleus accumbens of freely moving rats., (© 2022 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

A bis(μ-oxo)diiron(IV,IV) complex as a model for intermediate Q in the methane monooxygenase reaction cycle has been prepared. The precursor complex with a [Fe III Fe IV (μ-O) 2 ] core was fully characterized by X-ray crystallography and other spectroscopic analyses and was converted to the [Fe IV 2 (μ-O) 2 ] complex via electrochemical oxidation at 1000 mV (vs Ag/Ag + ) in acetone at 193 K. The UV-vis spectral features, Mössbauer parameters (Δ E Q = 2.079 mm/s and δ = -0.027 mm/s), and EXAFS analysis (Fe-O/N = 1.73/1.96 Å and Fe···Fe = 2.76 Å) support the structure of the low-spin ( S = 1, for each Fe) [Fe IV 2 (μ-O) 2 ] core. The rate constants of the hydrogen abstraction reaction from 9,10-dihydroanthracene at 243 K suggest the high reactivity of these synthetic bis(μ-oxo)diiron complexes supported by simple N4 tripodal ligand.

Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a devastating and life-threatening condition during its clinical course. Biomarkers for precisely anticipating the prognosis of AE-IPF remain to be fully established. The objective of this study was to clarify whether S100A8 and S100A9, which are calcium-binding proteins mainly produced by activated neutrophils, are significant prognostic biomarkers in AE-IPF., Methods: Thirty-seven patients with AE-IPF who were diagnosed and treated at our hospital were retrospectively evaluated. The serum levels of S100A8 and S100A9 were measured using enzyme-linked immunosorbent assay, and the relationships between these levels and clinical parameters or prognosis were evaluated., Results: The serum levels of S100A8 (median 386.5 ng/mL) and S100A9 (median 60.2 ng/mL) in patients with AE-IPF were significantly higher than those in age-matched healthy controls and in patients at IPF diagnosis (p < 0.001 for all combinations). The serum levels of S100A8 negatively correlated with percent forced vital capacity (r = -0.356, p = 0.049) and positively correlated with peripheral white blood cell number (r = 0.509, p = 0.002). Immunohistochemical staining of autopsy lung specimens showed that neutrophils, present mainly in the alveolar septum, were positive for S100A8 and S100A9. Patients with AE-IPF with higher levels of S100A8 or S100A9 showed significantly worse 3-month survival than those with lower levels (log-rank test, both p = 0.028). Finally, in multivariate analysis, the serum levels of both S100A8 and S100A9 were significant prognostic factors (hazard ratio 4.032, p = 0.023 and hazard ratio 4.327, p = 0.012)., Conclusion: The serum levels of S100A8 and S100A9 at AE were significant prognostic biomarkers in patients with AE-IPF., Competing Interests: Conflict of Interest All authors do not have any potential conflicts of interest. This research was not funded., (Copyright © 2021 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Purpose: IL-33 is known to induce corticosteroid-resistant eosinophilic inflammation and airway remodeling by activating type 2 innate lymphoid cells (ILC2s). Although the RAS signal pathway plays an important role in IL-33-induced ILC2s activation and airway remodeling, it is not known if RAS inhibitors are effective against refractory asthma. We examined the effects of the RAS inhibitor XRP44X in refractory asthma. Methods: RAS activity were examined by BAL fluid and T-cells isolated from spleen cells in Dermatophagoides pteronyssinus (Dp)-sensitized/challenged acute allergic airway inflammation model. A chronic allergic airway inflammation mouse model was generated by challenged with Dp. XRP44X and/or fluticasone were administrated nasally to different experimental groups. The effects of nasal simultaneous administration of XRP44X or fluticasone were assessed in mice administrated with IL-33 or Dp. Results: RAS activity in CD4 + T cells stimulated by Dp were suppressed by XRP44X. Although fluticasone and XRP44X only improved allergic airway inflammation in mice, XRP44X in combination with fluticasone produced further improvement in not only eosinophilic inflammation but also bronchial subepithelial thickness. XRP44X suppressed IL-5 and IL-13 production from ILC2s, although this effect was not suppressed by fluticasone. IL-33-induced airway inflammation resistant to fluticasone was ameliorated by XRP44X via regulating the accumulation of lung ILC2s. Conclusion: The RAS signal pathway plays a crucial role in allergen-induced airway remodeling associated with ILC2s. XRP44X may have therapeutic potential for refractory asthma.

Bare TiO 2 photocatalyst almost quantitatively converted nitrobenzene to aniline with various saccharides without the use of hydrogen gas. Although aniline was formed when any saccharide was used, the use of disaccharides (lactose, maltose, and sucrose) decreased the reaction rate. The rate of photocatalytic hydrogenation of nitrobenzene using saccharides is determined by the degradation rate of saccharides at positive holes. When glucose was used, formic acid, arabinose, glyceraldehyde and lactic acid were obtained, which are products that are consistent with the product of the photocatalytic oxidation of glucose., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Antifibrotic therapy (AFT) slows disease progression in patients with idiopathic pulmonary fibrosis (IPF). The Gender-Age-Physiology (GAP) index, was developed based on data at IPF diagnosis before the introduction of AFT and has not been evaluated in the AFT context. Further, recent advances have revealed the importance of body-composition factors in prognosis of IPF treated with AFT. This multi-centre, retrospective study aimed to evaluate the GAP index and body mass index (BMI) at the time of AFT initiation for predicting prognosis in patients with IPF. This study included two patient cohorts of IPF receiving AFT, Hamamatsu cohort (n = 110) and Seirei cohort (n = 119). The distribution of GAP stages I, II, and III was 38.2%, 43.6%, and 18.2%, respectively, in Hamamatsu cohort; in Seirei cohort, it was 41.2%, 50.4%, and 8.4%, respectively. In both cohorts, the GAP index distinctly classified prognosis into three groups (log-rank test). Interestingly, a lower BMI showed prognostic value independent of the GAP index in multivariate analyses. Subsequently, combining the GAP index with BMI at AFT initiation successfully divided the patients with IPF into four distinct prognoses. Assessment of the GAP index and BMI measurement at AFT initiation are important for predicting prognosis in patients with IPF., (© 2021. The Author(s).)

The nucleus accumbens (NAc) is a terminal region of mesocorticolimbic dopamine (DA) neuronal projections from the ventral tegmental area. Accumbal DA release is integrated by afferents from other brain regions and by interneurons, which involve a diversity of neurotransmitters and neuropeptides. These integrative processes, implicated in the pathobiology of neuropsychiatric disorders, are mediated via receptor subtypes whose relative roles in the regulation of accumbal DA release are poorly understood. Such complex interactions are exemplified by how selective activation of opioid receptor subtypes enhances accumbal DA efflux in a manner that is modulated by changes in neural activity through GABA receptor subtypes. This review delineates the roles of GABA A and GABA B receptors in GABAergic neural mechanisms in NAc that participate in delta- and mu-opioid receptor-mediated increases in accumbal DA efflux in freely moving rats, focusing on studies using in vivo brain microdialysis. First, we consider how endogenous GABA exerts inhibition of accumbal DA efflux through GABA receptor subtypes. We also consider possible intra-neuronal source of the endogenous GABA that inhibits accumbal DA efflux. As NAc contains GABAergic neurons that express delta- or mu-opioid receptors, inhibition of accumbal GABAergic neurons is a candidate for mediating delta- or mu-opioid receptor-mediated increases in accumbal DA efflux. Therefore, we provide a detailed analysis of the effects of GABA receptor subtype ligands on delta- and mu-opioid receptor-mediated accumbal DA efflux. Finally, we present an integrative model to explain the mechanisms of interaction among delta- and mu-opioid receptors, GABAergic neurons and DAergic neurons in NAc., (© 2021. Maj Institute of Pharmacology Polish Academy of Sciences.)

Background: Currently, there are two antifibrotics used to treat idiopathic pulmonary fibrosis (IPF): pirfenidone and nintedanib. Antifibrotics slow disease progression by reducing the annual decline of forced vital capacity (FVC), which possibly improves outcomes in IPF patients. During treatment, patients occasionally switch antifibrotic treatments. However, prognostic implication of changing antifibrotics has not yet been evaluated., Methods: This multi-center retrospective cohort study examined 262 consecutive IPF patients who received antifibrotic therapy. Antifibrotic agents were switched in 37 patients (14.1%). The prognoses were compared between the patient cohort that switched antifibrotics (Switch-IPF) and those without (Non-Switch-IPF) using propensity-score matched analyses., Results: The median period between the initiation of antifibrotic therapy and the drug switch was 25.8 (12.7-35.3) months. The most common reasons for the switch were disease progression (n = 17) followed by gastrointestinal disorders (n = 12). Of the 37 patients that switched antifibrotics, only eight patients disrupted switched antifibrotics by their adverse reactions. The overall prognosis of the Switch-IPF cohort was significantly better than the Non-Switch-IPF cohort (median periods: 67.2 vs. 27.1 months, p < 0.0001). In propensity-score matched analyses that were adjusted to age, sex, FVC (%), history of acute exacerbation, and usage of long-term oxygen therapy, the Switch-IPF cohort had significantly longer survival times than the Non-Switch-IPF group (median 67.2 vs. 41.3 months, p = 0.0219). The second-line antifibrotic therapy showed similar survival probabilities than those in first-line antifibrotic therapy in multistate model analyses., Conclusion: Switching antifibrotics is feasible and may improve prognosis in patients with IPF. A further prospective study will be required to confirm clinical implication of switching the antifibrotics., (© 2021. The Author(s).)

Flavor and nutritional quality has been negatively impacted during the course of domestication and improvement of the cultivated tomato ( Solanum &nbsp; lycopersicum ). Recent emphasis on consumers has emphasized breeding strategies that focus on flavor-associated chemicals, including sugars, acids, and aroma compounds. Carotenoids indirectly affect flavor as precursors of aroma compounds, while chlorophylls contribute to sugar production through photosynthesis. However, the relationships between these pigments and flavor content are still unclear. In this study, we developed a simple and high-throughput method to quantify chlorophylls and carotenoids. This method was applied to over one hundred tomato varieties, including S . lycopersicum and its wild relatives ( S . l . var. cerasiforme and S . pimpinellifolium ), for quantification of these pigments in fruits. The results obtained by integrating data of the pigments, soluble solids, sugars, and aroma compounds indicate that (i) chlorophyll-abundant varieties have relatively higher sugar accumulations and (ii) prolycopene is associated with an abundance of linear carotenoid-derived aroma compounds in one of the orange-fruited varieties, "Dixie Golden Giant". Our results suggest the importance of these pigments not only as components of fruit color but also as factors influencing flavor traits, such as sugars and aroma.

Cacao polyphenols (CPs) are known to suppress the oxidation of low-density lipoprotein and cholesterol absorption. Herein, we examined the impact of CP on the lipid metabolism in rats fed CP-rich chocolate, by analyzing liver weight and histology, via hematoxylin-eosin staining. The high-CP group had significantly lighter livers than the CP-free group. Histologically, the high-CP group showed significantly lower liver fat accumulation than the CP-free group. These results suggest that CPs prevent liver fat accumulation, being potentially useful against obesity and related diseases.

Objectives: Natriuretic peptides are an important prognostic marker in patients with heart failure (HF). However, little is known regarding their prognostic significance in patients with atrial fibrillation (AF) without HF and natriuretic peptides levels are underused in these patients in daily practice., Methods: The Fushimi AF Registry is a community-based prospective survey of patients with AF in Fushimi-ku, Kyoto, Japan. We investigated patients with AF without HF (defined as prior HF hospitalisation, New York Heart Association functional class≥2 or left ventricular ejection fraction<40%) using the data of B-type natriuretic peptide (BNP, n=388) or N-terminal pro-B-type natriuretic peptide (NT-proBNP, n=771) at enrolment. BNPs were converted to NT-proBNP using a conversion formula. We divided the patients according to quartiles of NT-proBNP levels and compared the backgrounds and outcomes., Results: Of 1159 patients (mean age: 72.1±10.2 years, median CHA 2 DS 2 -VASc score: 3 and oral anticoagulant (OAC) prescription: 671 (56%)), the median NT-proBNP level was 488 (IQR 169-1015) ng/L. Patients with high NT-proBNP levels were older, had higher CHA 2 DS 2 -VASc scores and had more OAC prescription (all p<0.001). Kaplan-Meier curves demonstrated that NT-proBNP levels were significantly associated with higher incidences of stroke/systemic embolism, all-cause death and HF hospitalisation during a median follow-up period of 5.0 years (log rank, all p<0.001). Multivariable Cox regression analyses revealed that NT-proBNP levels were an independent predictor of adverse outcomes even after adjustment by various confounders., Conclusion: NT-proBNP levels are a significant prognostic marker for adverse outcomes in patients with AF without HF and may have clinical value., Trial Registration Number: UMIN000005834., Competing Interests: Competing interests: MAk received lecture fees from Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer Healthcare and Daiichi-Sankyo., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Gastroesophageal reflux disease is a common condition, and proton pump inhibitors (PPIs) are the mainstays of treatment. However, concerns have been raised about the safety of PPIs. A potassium-competitive acid blocker (P-CAB), vonoprazan (VPZ), was recently introduced, which may provide clinical benefits. This study was performed to investigate the cost-effectiveness of alternative long-term strategies including continuous and discontinuous treatment with VPZ for the management of reflux esophagitis in Japan., Methods: A health state transition model was developed to capture the long-term management of reflux esophagitis. Four different strategies were compared: (a) intermittent PPI using lansoprazole (LPZ); (b) intermittent P-CAB; (c) maintenance PPI using LPZ; and (d) maintenance P-CAB., Results: Intermittent P-CAB was the most cost-effective, and the number of days for which medication was required with this strategy was fewest. Maintenance PPI was more efficacious, but more costly than intermittent P-CAB. Maintenance P-CAB was more efficacious, but more costly than maintenance PPI. Co-payments were higher for maintenance PPI than for intermittent P-CAB, and for maintenance P-CAB than for maintenance PPI, which were considered reasonable for the majority of patients to improve symptoms., Conclusions: Intermittent P-CAB appears to be the strategy of choice for the majority of reflux esophagitis patients in clinical practice. If a patient is not satisfied with the symptom control of the current strategy, switching to a more effective strategy appears to be a reasonable option for the majority of patients., Competing Interests: The authors have stated explicitly that there are no conflicts of interest in connection with this article., (© 2021 The Authors. Journal of General and Family Medicine published by John Wiley & Sons Australia, Ltd on behalf of Japan Primary Care Association.)

The patient was an 82-year-old Japanese man with no family history suggestive of amyloidosis. He developed bilateral leg edema and shortness of breath and was referred to our hospital. An electrocardiogram showed atrial fibrillation with right bundle branch block. Echocardiography showed concentric LV hypertrophy. An endomyocardial biopsy showed severe ATTR amyloid deposits. A genetic analysis of the transthyretin (TTR) gene revealed a heterozygous c.187C>T missense variant resulting in p.P63S (P43S). In silico analyses predicted that this variant only modestly altered the structure and function of the TTR protein. The p.P63S variant might be associated with an elderly-onset cardiac-dominant ATTRv phenotype.

Background and Objective: Recent research has highlighted the fundamental role of sarcopenia, characterized by loss of skeletal muscle mass and strength, with a risk of poor outcomes. AFT preserves lung function by preventing the annual decline in FVC and is associated with improved outcomes in patients with IPF. However, altered cause of death and prognostic implications of sarcopenia in patients with IPF receiving AFT remain unknown., Methods: This study comprised two cohorts of patients with IPF receiving AFT, historical cohort of IPF patients without AFT and controls. The cause of mortality was compared with a historical cohort. Sarcopenia was assessed by measuring the ESM CSA and ESM MA via CT., Results: Patients with IPF had smaller ESM CSA and lower ESM MA but similar BMI than controls, suggesting patients with IPF had skeletal muscle loss without any obvious body weight loss. The most common cause of mortality in patients receiving AFT was chronic respiratory failure, accounting for approximately 60%, and decreased proportions of LC were found. Subsequently, low ESM CSA was an independent prognostic factor associated with worse survival rates. Furthermore, combined assessment of ESM CSA , %FVC predicted and BMI values provided clear prognostic distinction., Conclusion: Patients with IPF receiving AFT showed skeletal muscle loss without obvious weight loss. These patients mostly died by chronic respiratory failure, and skeletal muscle wasting has prognostic significance, suggesting that preventing sarcopenia as well as preserving lung function are important for managing these patients., (© 2020 Asian Pacific Society of Respirology.)

Background: Heart rate (HR) is an important factor in atrial fibrillation (AF); however, it remains unclear whether the impact of HR differs between paroxysmal AF and sustained (persistent and permanent) AF., Methods and results: The association of resting HR during AF with adverse events (composite of all-cause death, hospitalization for heart failure, stroke/systemic embolisms, myocardial infarction, and arrhythmic events) in 1,064 paroxysmal and 1,610 sustained AF patients from the Fushimi AF Registry were investigated. These patients were divided into 4 groups based on their resting HR; ≥110 beats/min (bpm), 80-109 bpm, 60-79 bpm, and <60 bpm. The number of patients in each group was 486, 400, 172, and 22 for paroxysmal AF, and 205, 734, 645, and 71 for sustained AF, respectively. Among patients with sustained AF, a HR ≥110 bpm was associated with a higher incidence of adverse events at 1 year and during the entire follow up (median of 1,833 days) (hazard ratio [95% confidence interval] compared with a HR of 60-79 bpm: 1.90 [1.31-2.72] at 1 year, 1.38 [1.10-1.72] during the entire follow up). Patients with a HR <60 bpm showed higher incidence of adverse events at 1 year; however, the incidence of adverse events did not differ among all HR groups of paroxysmal AF., Conclusions: Baseline HR was associated with adverse events in sustained AF, but not in paroxysmal AF.

To develop a high-performance hydrogen gas sensor, we fabricated a composite film made of carbon nanotubes (CNTs) and palladium nanoparticles. Carbon nanotubes were spin-coated onto a glass substrate, and subsequently, palladium nanoparticles were sputtered onto this film. The response to hydrogen gas was measured during two seasons (summer and winter) using a vacuum chamber by introducing a hydrogen/argon gas mixture. There was a clear difference in the sensor response despite the temperature difference between summer and winter. In addition, since a clean chamber was used, fewer water molecules acted as a dopant, and the behavior of the CNT changed from p-type to n-type because of the dissociative adsorption of hydrogen. This phenomenon was confirmed as the Seebeck effect. Finally, the work functions of Pd, PdH x , and CNT were calculated by first-principle calculations. As predicted by previous studies, a decrease in work function due to hydrogen adsorption was confirmed; however, the electron transfer to CNT was not appropriate from the perspective of charge neutrality and was found to be localized at the Pd/CNT interface. It seems that the Seebeck effect causes the concentration of conductive carriers to change.

Cervical cancer (CC) is usually initiated by infection with high-risk types of human papillomavirus (HPV). The HPV E6 and E7 proteins target p53 and RB, respectively, but other cellular targets likely exist. We generated uterus-specific MOB1A/B double KO (uMob1DKO) mice, which immediately developed cervical squamous cell carcinoma in situ. Mutant cervical epithelial cells showed YAP1-dependent hyperproliferation, altered self-renewal, impaired contact inhibition, and chromosomal instability. p53 activation was increased in uMob1DKO cells, and additional p53 loss in uMob1DKO mice accelerated tumor invasion. In human CC, strong YAP1 activation was observed from the precancerous stage. Human cells overexpressing HPV16 E6/E7 showed inactivation of not only p53 and RB but also PTPN14, boosting YAP1 activation. Estrogen, cigarette smoke condensate, and PI3K hyperactivation all increased YAP1 activity in human cervical epithelial cells, and PTPN14 depletion along with PI3K activation or estrogen treatment further enhanced YAP1. Thus, immediate CC onset may initiate when YAP1 activity exceeds an oncogenic threshold, making Hippo-YAP1 signaling a major CC driver., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Motor neuron diseases are a group of progressive neurological disorders that degenerate motor neurons. The neuroblastoma × spinal cord hybrid cell line NSC-34 is widely used as an experimental model in studies of motor neuron diseases. However, the differentiation efficiency of NSC-34 cells to neurons is not always sufficient. We have found that prostaglandin E 2 (PGE 2 ) induces morphological differentiation in NSC-34 cells. The present study investigated the functional properties of PGE 2 -differentiated NSC-34 cells. Retinoic acid (RA), a widely-used agent inducing cell differentiation, facilitated neuritogenesis, which peaked on day 7, whereas PGE 2 -induced neuritogenesis took only 2 days to reach the same level. Whole-cell patch-clamp recordings showed that the current threshold of PGE 2 -treated cell action potentials was lower than that of RA-treated cells. PGE 2 and RA increased the protein expression levels of neuronal differentiation markers, microtubule-associated protein 2c and synaptophysin, and to the same extent, motor neuron-specific markers HB9 and Islet-1. On the other hand, protein levels of choline acetyltransferase and basal release of acetylcholine in PGE 2 -treated cells were higher than in RA-treated cells. These results suggest that PGE 2 is a rapid and efficient differentiation-inducing factor for the preparation of functionally mature motor neurons from NSC-34 cells.

Background: Severe intractable tics, which are associated with Tourette syndrome and chronic tic disorder (TS/CTD), severely affect the quality of life. Common less-invasive treatments are often unable to attenuate tics with deep brain stimulation currently being the only effective treatment. We aimed to assess the anti-tic effect of deep slow nasal respiration with tight lip closure using patients with TS/CTD., Methods: We retrospectively analyzed 10 consecutive patients (9 men, 1 woman; 23-41 years old). We instructed the patients to perform the procedure for 120 s and to obtain a video recording of before and during the procedure. The videos were used to count tics and determine lip competency or incompetency. The counted tics were rated using the modified Rush Video Rating Scale., Results: Compared with before the procedure, there were significantly lower frequencies of motor and phonic tics, as well as video scored, during the procedure. Eight patients presented with lip incompetency before the procedure and none after the procedure (P = 0.041). There were no side effects associated with the procedure., Conclusion: Our findings indicate that deep slow nasal respiration with tight lip closure ameliorates tics in patients with TS/CTD. In accordance with our results, lip opening and oral breathing could be causes of tics, in addition to heritability. Therefore, this novel procedure could improve tics. Furthermore, our findings could contribute toward the development of tic treatments and elucidate their pathophysiology regarding the reward system, hypersensitivity, autonomic nerves, and nasal airway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Antithrombotic therapies that are optimal for atrial fibrillation (AF) patients undergoing percutaneous coronary intervention (PCI) have been studied but remain uncertain. We often encounter difficulties in choosing an appropriate antithrombotic therapy with antiplatelet agents after PCI in AF patients treated with oral anticoagulant due to a high CHADS 2 score. Since there are no data on the incidences of PCI procedures in AF patients, we evaluated those incidences as well as the association between PCI and the CHADS 2 score using data from the Fushimi AF Registry., Methods: The Fushimi AF Registry is a community-based prospective cohort study of AF patients in Fushimi-ku, Kyoto, Japan. Follow-up data were available for 4325 patients, and the median follow-up was 3.6 (interquartile range: 1.9-5.9) years., Results: There were 143 PCI procedures performed in 122 patients during follow-up, and 28 (20%) were emergent ones. The crude incidence of PCI procedures was 9.36 per 1000 person-years. At 1 and 3 years, the cumulative incidences of PCI were 46 (1.1%) and 85 (2.4%), respectively. As for 4 age groups: <65 (n = 765), 65-75 (n = 1359), 75-85 (n = 1586), and 85≤ years (n = 615), the rates of PCI were 0.4%, 1.4%, 1.4%, and 0.6% at 1 year, and were 1.4%, 2.7%, 2.8%, and 1.6% at 3 years, respectively. The incidence of PCI procedures in patients with a CHADS 2 score ≥2 (n = 2651, 61.3%) was higher than that in patients with a CHADS 2 score ≤1 (n = 1674, 38.7%). Among the factors making up the CHADS 2 score, only diabetes mellitus was associated with PCI procedures in patients with AF (hazard ratio, 1.95; 95% confidence interval, 1.34-2.83; p = 0.0005)., Conclusions: About 1 in 100 AF patients underwent PCI annually, and patients with a CHADS 2 score ≥2 were associated with higher incidences of PCI procedures., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: There is a growing burden of valvular heart disease (VHD) and atrial fibrillation (AF) due to population aging, but data regarding the characteristics and outcomes of patients with AF and concomitant VHD are lacking., Methods and results: The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, Kyoto. Among 3,566 patients with available echocardiographic data, 20% had VHD, consisting of 131 valvular AF (VAF: 3.7%) and 583 nonvalvular AF with VHD (NVAF-VHD: 16.3%). Here, VAF was defined as AF with mitral stenosis or a prosthetic heart valve. AF patients with VHD were older, had more comorbidities with a higher CHADS 2 score, and were prescribed oral anticoagulants more frequently than those without VHD. After adjusting for confounders, VHD was not associated with stroke or systemic embolism, all-cause mortality, or cardiac death. NVAF-VHD was significantly associated with an increased risk of hospitalization for heart failure (adjusted hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.16-1.78), whereas VAF was not (HR, 1.28; 95% CI, 0.86-1.92). Among all types of VHD, aortic valve diseases were associated with a higher risk of cardiac events, whereas mitral valve diseases were not., Conclusions: Although VHD did not significantly affect thromboembolism or mortality, it affected cardiac events depending on type, with aortic valve diseases having higher risk, in Japanese patients with AF.

Invasion of the endobronchial mucosa by cancer cells is frequently seen in small cell lung cancer (SCLC), but an intraluminal polypoid growth pattern is extremely rare. We herein describe the case of a 69-year-old woman with limited-stage SCLC who had a pedunculated mass in the orifice of the right upper bronchus. Thin-section CT of the lung showed an endobronchial protruding mass accompanied by tubular and branching opacities (the so-called finger-in-glove sign) in the right upper lobe bronchus, which were enhanced by contrast media. She responded well to chemotherapy with concurrent radiation therapy. Although very rare, SCLC patients can have intraluminal polypoid growth, as was observed in this case.

Aims: Orexin-A is known to induce anti-nociceptive effects in animal models of chronic pain. We have found that orexin-A inhibits KCl loading-induced increases in the intracellular calcium ion levels ([Ca 2+ ] i ) in C-fiber-like neurons of rats showing inflammatory nociceptive behavior. Here, we examined the effects of orexin-A on the depolarization of C-fiber-like neurons derived from a rat model for another type of chronic pain, namely neuropathic pain. Thus, we analyzed the effects of orexin-A on KCl-induced increases in [Ca 2+ ] i in C-fiber-like neurons of rats with sciatic nerve ligation., Methods: Paw withdrawal and threshold force in response to tactile stimuli were evaluated using von Frey filaments. Sham-operated rats served as controls. [Ca 2+ ] i in neurons were visualized by calcium fluorescent probe. Changes in [Ca 2+ ] i were assessed using relative fluorescence intensity., Results: Seven days after sciatic nerve ligation, paw withdrawal and threshold force for tactile stimuli were increased and reduced, respectively. KCl loading to neurons from either sciatic nerve-ligated or control rats increased relative fluorescence intensity. The KCl-induced increase in relative fluorescence intensity in sciatic nerve-ligated, but not that of control, rats was inhibited by orexin-A. The OX 1 and OX 2 receptor antagonist MK-4305 and OX 2 receptor antagonist EMPA, but not the OX 1 receptor antagonist SB 334867, each counteracted orexin-A-induced inhibition of KCl-provoked increases in relative fluorescence intensity., Conclusion: The present findings constitute neuropharmacological evidence that OX 2 but not OX 1 receptors mediate the inhibitory effects of orexin-A on KCl-induced increases in [Ca 2+ ] i in C-fiber-like neurons of rats showing hyperalgesia provoked by sciatic nerve ligation., (© 2019 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of NeuropsychoPharmacology.)

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease (ILD). Currently, two antifibrotic drugs are available for reducing forced vital capacity (FVC) decline in IPF. However, many pulmonologists wait before initiating treatment, especially when IPF patients have stable disease. This study aimed to investigate the impact on survival outcome of FVC decline and a slow rate of FVC decline prior to and following treatment with these two antifibrotic drugs., Methods: Out of the 235 IPF patients treated with antifibrotic therapy that were screened, 105 cases were eligible, who then underwent physiological evaluation at 6 months prior to and following antifibrotic therapy. Clinical characteristics and prognostic outcomes were compared among groups, and prognostic factors were evaluated using a Cox proportional hazards analysis., Results: In terms of %FVC decline prior to the therapy and a slow rate of FVC decline, there was no significant difference between stable and worsened groups and responder and non-responder groups, respectively. On the other hand, in terms of %FVC decline (decline >5%) following antifibrotic therapy, the stable/improved group had significantly better prognosis than the worsened group. Prognostic analysis revealed that a stable/improved status following antifibrotic therapy [HR: 0.35 (0.15-0.87)] was significantly associated with a better prognosis., Conclusions: Concerning the FVC decline prior to and following antifibrotic therapy and a slow rate of FVC decline, only the FVC decline following the therapy is associated with a greater survival outcome. An early treatment decision may thus be beneficial for IPF. The reviews of this paper are available via the supplemental material section.

Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is well known as a life-threatening condition during its clinical course. However, the clinical features and prognosis in AE of unclassifiable idiopathic interstitial pneumonia (AE-UCIIP) remain to be elucidated. The aim of this study was to clarify the clinical features and prognosis of AE-UCIIP compared with those of AE-IPF., Methods: In 187 patients with UCIIP or IPF, 64 patients with AE-UCIIP or AE-IPF, who were diagnosed and treated at our hospital, were retrospectively evaluated., Results: A total of 24 patients with AE-UCIIP were significantly older ( p  = 0.011), included more women ( p  < 0.001) and never-smokers ( p  < 0.001), and showed fewer lung lesions on high-resolution computed tomography ( p  = 0.006) than 40 patients with AE-IPF. Incidence of AE-UCIIP was 10.29%/year and was significantly higher than in AE-IPF (Gray's test, p  = 0.008). Prognosis of AE-UCIIP was as poor as that of AE-IPF (log-rank, p  = 0.681). Percent-predicted forced vital capacity (%FVC) [hazard ratio (HR) 0.934, p  = 0.045], and GAP stage within 12 months before AE (HR 3.530, p  = 0.023), and partial pressure arterial oxygen/fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio at AE (HR 0.998, p  = 0.016) were significant prognostic factors. Finally, commencement of long-duration (⩾12 h) direct hemoperfusion with a polymyxin B-immobilised fibre column (PMX-DHP) within 2 days after admission significantly improved survival (log-rank, p  = 0.038) and was a significant prognostic factor (HR 0.175, p  = 0.0039) in AE-UCIIP. Long-duration PMX-DHP showed favourable treatment effects even in the combined group of patients with AE-UCIIP or AE-IPF (log-rank p  = 0.002; HR 0.328, p  = 0.006)., Conclusions: Patients with AE-UCIIP were older and included more women and never-smokers than those with AE-IPF. Prognosis of AE-UCIIP was as poor as that of AE-IPF. The reviews of this paper are available via the supplemental material section.

Fibrocytes, which are bone marrow-derived collagen-producing cells, were reported to play a role in the pathogenesis of pulmonary fibrosis. However, their function in pulmonary fibrosis is unclear. We analyzed their function compared with that of monocytes and localization in fibrotic tissues in patients with idiopathic pulmonary fibrosis (IPF). We compared the gene expression profile of monocyte-derived fibrocytes with that of monocytes by microarray analysis. Proliferation and differentiation into myofibroblasts were examined by 3H-thymidine incorporation assay and Western blotting. We measured the level of growth factors in the culture supernatant of fibrocytes by ELISA. The localization of fibrocytes in lung tissues of patients with IPF was determined by immunofluorescence staining. Compared with monocytes, fibrocytes had higher expression of extracellular matrix- and growth factor-encoding genes, including PDGF-B, FGF-2 and VEGF-B. Although fibrocytes did not proliferate in response to PDGF, co-culture of fibrocytes stimulated the growth of lung fibroblasts through the production of PDGF-BB. In the lung of IPF patients, CD45+Collagen-I+FSP-1+ cells, which have a similar phenotype to fibrocytes, were detected and co-stained with anti-PDGF antibody. This study suggested that fibrocytes function in pulmonary fibrosis partly by producing PDGF in the lungs of IPF patients. J. Med. Invest. 67 : 102-112, February, 2020.

Chest computed tomography (CT) findings of minute pulmonary meningothelial-like nodules (MPMNs) usually show tiny nodules (2-5 mm in diameter) of ground-glass attenuation. However, diffuse, thin-walled cavities have rarely been reported. We herein report a 56-year-old woman with MPMNs showing diffuse, thin-walled cystic lesions on a thin-section chest CT scan. Clinicians need to be aware of the imaging characteristics of this conditions to guide appropriate management of lung diseases, as these CT findings may resemble certain metastatic lung neoplasias and primary adenocarcinoma of the lung.

Data regarding the relation of the type of atrial fibrillation (AF) to the incidence of cardiac events remain scarce. This study sought to investigate the association of AF type with the incidences of cardiac death and heart failure (HF) hospitalization between paroxysmal and sustained (persistent/permanent) AF in the overall population and in age subgroups (≤74, 75 to 84, and ≥85 years), using the data from a Japanese community-based prospective survey, the Fushimi AF Registry. The participants started to be enrolled since March 2011, and follow-up data were available for 4,304 patients by the end of November 2017. Patients with sustained AF (n = 2,187, 50.8%) had more co-morbidities with higher mean CHA 2 DS 2 -VASc score than those with paroxysmal AF (n = 2,117, 49.2%) (sustained vs paroxysmal: 3.57 ± 1.69 vs 3.17 ± 1.67, p <0.001). During a median follow-up of 1,307 (interquartile range: 709 to 2,156) days, the composite of cardiac death and HF hospitalization occurred more frequently in those with sustained AF (event rate: 5.1 vs 2.8 per 100 person-years; p <0.001). On multivariate analysis, sustained AF was independently associated with higher incidence of this composite end point (adjusted hazard ratio [HR]: 1.35, 95% confidence interval [CI]: 1.12 to 1.63, p = 0.002). In age subgroups, this association was observed only in the younger AF patients (≤74 years) (adjusted HR: 2.03, 95% CI: 1.44 to 2.86, p <0.001), but not in the older subgroups (p = 0.018 for interaction). In conclusion, sustained AF was associated with higher incidence of the composite of cardiac death and HF hospitalization than paroxysmal AF, with different relations seen depending on age subgroups., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose/Aim of the Study: Wnt/β-catenin signaling was reported to be activated in pulmonary fibrosis, and was focused on as a target for antifibrotic therapy. However, the mechanism how the inhibition of Wnt/β-catenin signaling ameliorate pulmonary fibrosis has not been fully elucidated. The purpose of this study is to explore the target cells of Wnt/β-catenin inhibition in pulmonary fibrosis and to examine the antifibrotic effect of the novel inhibitor PRI-724 specifically disrupting the interaction of β-catenin and CBP. Materials and Methods: The effect of C-82, an active metabolite of PRI-724, on the expression of TGF-β1 and α-smooth muscle actin (SMA) was examined on fibroblasts and macrophages. We also examined the effects of PRI-724 in mouse model of bleomycin-induced pulmonary fibrosis. Results: The activation and increased accumulation of β-catenin in the canonical pathway were detected in lung fibroblasts as well as macrophages stimulated by Wnt3a using Western blotting. Treatment with C-82 reduced CBP protein and increased p300 protein binding to β-catenin in the nucleus of lung fibroblasts. In addition, C-82 inhibited the expression of SMA in lung fibroblasts treated with TGF-β, indicating the inhibition of myofibroblast differentiation. In the fibrotic lungs induced by bleomycin, β-catenin was stained strongly in macrophages, but the staining of β-catenin in alveolar epithelial cells and fibroblasts was weak. The administration of PRI-724 ameliorated pulmonary fibrosis induced by bleomycin in mice when administered with a late, but not an early, treatment schedule. Analysis of bronchoalveolar fluid (BALF) showed a decreased number of alveolar macrophages. In addition, the level of TGF-β1 in BALF was decreased in mice treated with PRI-724. C-82 also inhibited the production of TGF-β1 by alveolar macrophages. Conclusions: These results suggest that the β-catenin/CBP inhibitor PRI-724 is a potent antifibrotic agent that acts by modulating the activity of macrophages in the lungs.

Cholinergic neurons in the nucleus accumbens contain GABA A and GABA B receptors that are thought to inhibit neural activity. We analyzed the roles of GABA A and GABA B receptors in regulating accumbal acetylcholine efflux of freely moving rats using in vivo microdialysis. The effects of GABA receptor ligands on the accumbal dopamine efflux were also analyzed because accumbal cholinergic and dopaminergic neurons could mutually interact. Drugs were applied intracerebrally through the dialysis probe. Doses of compounds indicate total amount administered (mol) during 30-60 min infusions. To monitor basal acetylcholine, a low concentration of physostigmine (50 nM) was added to the perfusate. GABA A receptor agonist muscimol (3 and 30 pmol) induced a dose-related decrease in accumbal acetylcholine. GABA B receptor agonist baclofen (30 and 300 pmol) also produced a dose-related decrease in acetylcholine. GABA A receptor antagonist bicuculline (60 pmol) which failed to alter baseline acetylcholine counteracted the muscimol (30 pmol)-induced decrease in acetylcholine. GABA B receptor antagonist 2-hydroxysaclofen (12 nmol) which failed to change baseline acetylcholine, counteracted the baclofen (300 pmol)-induced decrease in acetylcholine. Neither muscimol (30 pmol) nor baclofen (300 pmol) which reduced accumbal acetylcholine altered baseline accumbal dopamine. Neither bicuculline (60 pmol) nor 2-hydroxysaclofen (12 nmol) also affected the baseline dopamine. These results show that GABA A and GABA B receptors each exert inhibitory roles in the regulation of accumbal cholinergic neural activity. The present results also provides in vivo neurochemical evidence that stimulation of GABA A and GABA B receptors each reduce acetylcholine efflux without affecting dopamine efflux in the nucleus accumbens of freely moving rats., (© 2018 Wiley Periodicals, Inc.)