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The study involved the analysis of emotion-associated language in the UK Conservative and Labour party general election manifestos between 2000 to 2019. While previous research have shown a general correlation between ideological positioning and overlap of public policies, there are still conflicting results in matters of sentiments in such manifestos. Using new data, we present how valence level can be swayed by party status within government with incumbent parties presenting a higher frequency in positive emotion-associated words while negative emotion-associated words are more prevalent in opposition parties. We also demonstrate that parties with ideological similitude use positive language prominently further adding to the literature on the relationship between sentiments and party status.

Abstract The aim of this study was to investigate the association between pulse pressure (PP) and chronic kidney disease (CKD) progression among the general population in Japan. We conducted a population-based cohort study of the residents of Iki Island, Nagasaki, Japan, from 2008 to 2018. We identified 1042 participants who had CKD (estimated glomerular filtration rate(eGFR)

Abstract Background Cost sharing, including copayment and coinsurance, is often used to contain medical expenditure by decreasing unnecessary or excessive use of healthcare resources. Previous studies in Japan have reported the effects of a coinsurance rate reduction for healthcare from 30 to 10% on the demand for healthcare among 70–74-year-old individuals. However, the coinsurance rate for this age group has recently increased from 10 to 20%. This study aimed to estimate the economic impact of coinsurance rate revision on healthcare resource utilization. Methods We collected claims data from beneficiaries of the municipality National Health Insurance and the Japanese Health Insurance Association in Fukuoka Prefecture. We categorized subjects born between March 2, 1944 and April 1, 1944 into the 20% coinsurance rate reduction group and those born between April 2, 1944 and May 1, 1944 into the 10% reduction group. An interrupted time-series analysis for multiple groups was employed to compare healthcare resource utilization trends before and after coinsurance rate reduction at 70 years. Results The 10% coinsurance rate reduction led to a significant increase in healthcare expenditure for outpatient care. The 20% reduction group showed a significantly sharper increase in healthcare expenditure for outpatient care than the 10% reduction group. Similarly, the 10% coinsurance group significantly increased in the number of ambulatory visits. The 20% coinsurance rate reduction group had more frequent ambulatory care visits than the 10% reduction group. Conclusions These results suggest that increasing the coinsurance rate among the elderly would reduce outpatient healthcare resource utilization; however, it would not necessarily reduce overall healthcare resource utilization.

Abstract:: How do people change their healthcare behavior when a public health crisis occurs? Within a year of its emergence, coronavirus disease 2019 (COVID-19) has gradually infiltrated our lives and altered our lifestyles, including our healthcare behaviors. In Japan, which faces China across the East China Sea and accepted 924,800 Chinese tourists in January 2020, the emergence and spread of COVID-19 provides a unique opportunity to study people's reactions and adaptations to a pandemic.Patients with chronic illnesses who require regular doctor visits are particularly affected by such crises. We focused on diabetic patients whose delay in routine healthcare invites life-threatening complications and examined how their patterns of doctor visits changed and how demographic, socioeconomic, and vital factors disparately affected this process. We relied on the insurance claims data of a health insurance association in Tokyo. By using panel data of diabetic patients from April 2018 to September 2020, we performed visual investigations and conditional logistic regressions controlling for all time-invariant individual characteristics.Contrary to the general notion that the change in healthcare behavior correlates with the actual spread of the pandemic, the graphical and statistical results both showed that diabetic patients started reducing their doctor visits during the early stage of the pandemic. Furthermore, a substantial decrease in doctor visits was observed in women, and large to moderate reductions were seen in patients who take insulin and are of advanced age, who are at high risk of developing severe COVID-19. By contrast, no differentiated effect was found in terms of income status. We further investigated why a change in pattern occurred for each subgroup.The patterns of routine healthcare revealed by this study can contribute to the improvement of communication with the target population, the delivery of necessary healthcare resources, and the provision of appropriate responses to future pandemics. (299 words).

Abstract Aims/Introduction The present study aimed to evaluate the effects of income levels on physician visit patterns and to quantify the consequent impact of irregular physician visits on glycemic control among employees’ health insurance beneficiaries in Japan. Materials and Methods We obtained specific health checkup data of untreated diabetes patients from the Fukuoka branch of the Japanese Health Insurance Association. We selected 2,981 insurance beneficiaries and classified 650 and 2,331 patients into, respectively, the regular visit and irregular visit group. We implemented propensity score matching to select an adequate control group. Results Compared with those with a standard monthly income

Background This large‐scale observational study on negative events in a real‐world setting investigated Japanese patients with atrial fibrillation who were not on anticoagulants. This study aims to evaluate the incidence of ischemic stroke and bleeding events (intracranial hemorrhage, gastrointestinal bleeding, others) based on CHA2DS2‐VASc scores in Japanese patients with atrial fibrillation who were not anticoagulated. Methods and Results We used health checkups and insurance claim data from a Japanese insurance organization. Altogether, 9733 atrial fibrillation patients were not prescribed anticoagulation during their follow‐up periods. Patients’ risk levels were defined by their CHA2DS2‐VASc scores (range 0–≥3): Men with scores of 0, 1, or ≥2 and women with scores of 1, 2, or ≥3 were considered at low, intermediate, or high risk, respectively. Cox proportional hazards model was used to assess the association between the CHA2DS2‐VASc‐determined risk and the incidence of ischemic stroke and intracranial, gastrointestinal, and other bleeding. The mean 2.5‐year follow‐up revealed 143 ischemic strokes and 332 bleeding events. Annual event rates were 0.58% for ischemic stroke and 1.17% for total bleeding events. Annual incidence of ischemic stroke increased with elevated predicted risks based on CHA2DS2‐VASc scores: 0.18% for low‐risk, 0.44% intermediate‐risk, and 1.29% high‐risk groups (P

Background. This study aimed to investigate the rate of first-generation H1-antihistamines use for older adults with dementia in Japan. Methods. The study design was retrospective cohort using claims data between fiscal years 2010 and 2013. Subjects were 75 years or older, diagnosed with dementia, and given H1-antihistamines orally during the study period after being diagnosed with dementia. We investigated the cumulative number of oral H1-antihistamines administered and the relationship between first-generation H1-antihistamine use and each explanatory variable using crude and adjusted odds ratio. Results. The cumulative total for use of first-generation H1-antihistamine for older adults with dementia accounted for 32.1% of all antihistamine medication. The majority of first-generation H1-antihistamine prescriptions were indicated for cold treatment. Those with upper respiratory infection or asthma had a significantly positive relationship with first-generation H1-antihistamine use. Conclusion. The study showed that first-generation H1-antihistamine drugs were highly prescribed in older adults with dementia in Japan.

We examined the impact of opportunistic infections on in-hospital mortality, hospital length of stay (LOS), and the total cost (TC) among adult T-cell leukaemia (ATL) patients. In this retrospective cohort study, we identified 3712 patients with ATL using national hospital administrative data. Analysed opportunistic infections included Aspergillus spp., Candida spp., cytomegalovirus (CMV), herpes simplex virus (HSV), pneumocystis pneumonia (PCP), tuberculosis, varicella zoster virus (VZV), Cryptococcus spp., nontuberculous mycobacteria, and Strongyloides spp. Multilevel logistic regression analysis for in-hospital mortality and a multilevel linear regression analysis for LOS and TC were employed to determine the impact of opportunistic infections on clinical outcomes and healthcare resources. We found ATL patients infected with CMV had significantly higher in-hospital mortality (adjusted odds ratio (AOR) 2.29 [1.50-3.49] p < 0.001), longer LOS (coefficient (B): 0.13 [0.06-0.20] p < 0.001) and higher TC (B: 0.25 [0.17-0.32] p < 0.001) than those without CMV. Those with CAN and PCP were associated with a lower in-hospital mortality rate (AOR 0.72 [0.53-0.98] p = 0.035 and 0.54[0.41-0.73] p < 0.001, respectively) than their infections. VZV was associated with longer LOS (B: 0.13 [0.06-0.19] p < 0.001), while aspergillosis, HSV, or VZV infections were associated with higher TC (B: 0.16 [0.07-0.24] p < 0.001, 0.12 [0.02-0.23] p = 0.025, and 0.17 [0.10-0.24] p < 0.001, respectively). Our findings reveal that CMV infection is a major determinant of poor prognosis in patients affected by ATL.

Abstract Precision medicine has drastically changed cancer treatment strategies including KRAS-mutant cancers which have been undruggable for decades. While intrinsic or acquired treatment resistance remains unresolved in many cases, epigenome-targeted therapy may be an option to overcome. We recently discovered the effectiveness of blocking small ubiquitin-like modifier (SUMO) signaling cascade (SUMOylation) in MYC-expressing KRAS-mutant cancer cells using a SUMO-activating enzyme E inhibitor TAK-981 that results in SUMOylation inhibition. Interestingly, TAK-981 promoted the degradation of MYC via the ubiquitin–proteasome system. Moreover, combination therapy with TAK-981 and MEK inhibitor trametinib remarkably regressed xenografted KRAS-mutant tumors by accumulating DNA damage and inducing apoptosis. Whereas our recent study revealed immune-independent antitumor efficacy, we evaluated the immune responses of cancer cells and immune cells in this study. We found that TAK-981-induced MYC downregulation promoted the activation of STING followed by Stat1 and MHC class I in KRAS-mutant cancer cells. Activation of dendritic cells or T cells treated with TAK-981 was also verified by upregulated activation markers in dendritic cells or skew-toward effector-like phenotypes in T cells. Furthermore, the enhanced immune-dependent antitumor efficacy of the combination therapy with TAK-981 and trametinib was confirmed by infiltration of immune cells into tumor tissues and immunodepleting-test using immunodepleting antibodies in syngeneic immunocompetent mouse models. Together with our recent study and here, the findings support that combination inhibition of SUMOylation and MEK comprehensively conquers MYC-expressing KRAS-mutant cancers by both immune-dependent and immune-independent antitumor responses.

Abstract Background Clinical amyopathic dermatomyositis is characterized by cutaneous symptoms but lacks muscle symptoms. Anti-melanoma differentiation-associated gene 5 antibodies are frequently found in Japanese patients with clinical amyopathic dermatomyositis. Patients with rapidly progressive interstitial lung disease with positive anti-melanoma differentiation-associated gene 5 antibodies have poor prognoses, and majority of them are treated with combination immunosuppressive therapy; however, the best treatment is yet to be determined. Case presentation A 52-year-old Asian male patient presented with a chief complaint of dyspnea on exertion. He had a typical skin rash and rapidly progressive interstitial pneumonia. Additionally, anti-melanoma differentiation-associated gene 5 antibodies were detected; therefore, he was diagnosed with dermatomyositis-associated interstitial pneumonia. Respiratory failure worsened despite administering steroid pulse therapy, tacrolimus, and cyclophosphamide. Consequently, plasma exchange was performed on day 13 of admission. After a slight improvement, the patient’s respiratory failure worsened. Thus, cyclophosphamide was replaced by tofacitinib on day 28. Although respiratory failure improved and the progression of interstitial pneumonia seemed under control, βD-glucan level increased and Aspergillus antigen was detected on day 49. Micafungin and voriconazole were administered, but the patient succumbed to worsening respiratory failure on day 61. The pathological autopsy revealed multiple nodular lesions with cavity formation in both lungs and the presence of Aspergillus with severe neutrophilic infiltration and necrosis, which supported the diagnosis of invasive pulmonary aspergillosis. Conclusion The patient with anti-melanoma differentiation-associated gene 5 antibody-related rapidly progressive interstitial lung disease, whose disease was difficult to control after the administration of triple immunosuppressive therapy (steroids, tacrolimus, and cyclophosphamide), showed good response with tofacitinib. Unfortunately, the patient died of invasive pulmonary aspergillosis owing to severe immunosuppression; thus, the signs of complications should be promptly detected.

Abstract Background KRAS mutations frequently occur in cancers, particularly pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer. Although KRAS G12C inhibitors have recently been approved, effective precision therapies have not yet been established for all KRAS-mutant cancers. Many treatments for KRAS-mutant cancers, including epigenome-targeted drugs, are currently under investigation. Small ubiquitin-like modifier (SUMO) proteins are a family of small proteins covalently attached to and detached from other proteins in cells via the processes called SUMOylation and de-SUMOylation. We assessed whether SUMOylation inhibition was effective in KRAS-mutant cancer cells. Methods The efficacy of the first-in-class SUMO-activating enzyme E inhibitor TAK-981 (subasumstat) was assessed in multiple human and mouse KRAS-mutated cancer cell lines. A gene expression assay using a TaqMan array was used to identify biomarkers of TAK-981 efficacy. The biological roles of SUMOylation inhibition and subsequent regulatory mechanisms were investigated using immunoblot analysis, immunofluorescence assays, and mouse models. Results We discovered that TAK-981 downregulated the expression of the currently undruggable MYC and effectively suppressed the growth of MYC-expressing KRAS-mutant cancers across different tissue types. Moreover, TAK-981-resistant cells were sensitized to SUMOylation inhibition via MYC-overexpression. TAK-981 induced proteasomal degradation of MYC by altering the balance between SUMOylation and ubiquitination and promoting the binding of MYC and Fbxw7, a key factor in the ubiquitin–proteasome system. The efficacy of TAK-981 monotherapy in immunocompetent and immunodeficient mouse models using a mouse-derived CMT167 cell line was significant but modest. Since MAPK inhibition of the KRAS downstream pathway is crucial in KRAS-mutant cancer, we expected that co-inhibition of SUMOylation and MEK might be a good option. Surprisingly, combination treatment with TAK-981 and trametinib dramatically induced apoptosis in multiple cell lines and gene-engineered mouse-derived organoids. Moreover, combination therapy resulted in long-term tumor regression in mouse models using cell lines of different tissue types. Finally, we revealed that combination therapy complementally inhibited Rad51 and BRCA1 and accumulated DNA damage. Conclusions We found that MYC downregulation occurred via SUMOylation inhibition in KRAS-mutant cancer cells. Our findings indicate that dual inhibition of SUMOylation and MEK may be a promising treatment for MYC-expressing KRAS-mutant cancers by enhancing DNA damage accumulation.

Abstract Detailed investigation of extremely severe pathological conditions in ancient human skeletons is important as it could shed light on the breadth of potential interactions between humans and disease etiologies in the past. Here, we applied palaeoproteomics to investigate an ancient human skeletal individual with severe oral pathology, focusing our research on bacterial pathogenic factors and host defense response. This female skeleton, from the Okhotsk period (i.e., fifth to thirteenth century) of Northern Japan, poses relevant amounts of abnormal dental calculus deposition and exhibits oral dysfunction due to severe periodontal disease. A shotgun mass-spectrometry analysis identified 81 human proteins and 15 bacterial proteins from the calculus of the subject. We identified two pathogenic or bioinvasive proteins originating from two of the three “red complex” bacteria, the core species associated with severe periodontal disease in modern humans, as well as two additional bioinvasive proteins of periodontal-associated bacteria. Moreover, we discovered defense response system-associated human proteins, although their proportion was mostly similar to those reported in ancient and modern human individuals with lower calculus deposition. These results suggest that the bacterial etiology was similar and the host defense response was not necessarily more intense in ancient individuals with significant amounts of abnormal dental calculus deposition.

Abstract Deep ocean water (DOW) exerts positive effects on the growth of marine organisms, suggesting the presence of unknown component(s) that facilitate their aquaculture. We observed that DOW suppressed plasma cortisol (i.e., a stress marker) concentration in Japanese flounder (Paralichthys olivaceus) reared under high-density condition. RNA-sequencing analysis of flounder brains showed that when compared to surface seawater (SSW)-reared fish, DOW-reared fish had lower expression of hypothalamic (i.e., corticotropin-releasing hormone) and pituitary (i.e., proopiomelanocortin, including adrenocorticotropic hormone) hormone-encoding genes. Moreover, DOW-mediated regulation of gene expression was linked to decreased blood cortisol concentration in DOW-reared fish. Our results indicate that DOW activated osteoblasts in fish scales and facilitated the production of Calcitonin, a hypocalcemic hormone that acts as an analgesic. We then provide evidence that the Calcitonin produced is involved in the regulatory network of genes controlling cortisol secretion. In addition, the indole component kynurenine was identified as the component responsible for osteoblast activation in DOW. Furthermore, kynurenine increased plasma Calcitonin concentrations in flounders reared under high-density condition, while it decreased plasma cortisol concentration. Taken together, we propose that kynurenine in DOW exerts a cortisol-reducing effect in flounders by facilitating Calcitonin production by osteoblasts in the scales.

Abstract BiFe0.9Co0.1O3 is a promising material for an ultra-low-power-consumption nonvolatile magnetic memory device because local magnetization reversal is possible through application of an electric field. Here, changes in ferroelectric and ferromagnetic domain structures in a multiferroic BiFe0.9Co0.1O3 thin film induced by “water printing”, which is a polarization reversal method involving chemical bonding and charge accumulation at the interface between the liquid and the film, was investigated. Water printing using pure water with pH = 6.2 resulted in an out-of-plane polarization reversal from upward to downward. The in-plane domain structure remained unchanged after the water printing process, indicating that 71° switching was achieved in 88.4% of the observation area. However, magnetization reversal was observed in only 50.1% of the area, indicating a loss of correlation between the ferroelectric and magnetic domains because of the slow polarization reversal due to nucleation growth.

Abstract Compost is used worldwide as a soil conditioner for crops, but its functions have still been explored. Here, the omics profiles of carrots were investigated, as a root vegetable plant model, in a field amended with compost fermented with thermophilic Bacillaceae for growth and quality indices. Exposure to compost significantly increased the productivity, antioxidant activity, color, and taste of the carrot root and altered the soil bacterial composition with the levels of characteristic metabolites of the leaf, root, and soil. Based on the data, structural equation modeling (SEM) estimated that amino acids, antioxidant activity, flavonoids and/or carotenoids in plants were optimally linked by exposure to compost. The SEM of the soil estimated that the genus Paenibacillus and nitrogen compounds were optimally involved during exposure. These estimates did not show a contradiction between the whole genomic analysis of compost-derived Paenibacillus isolates and the bioactivity data, inferring the presence of a complex cascade of plant growth-promoting effects and modulation of the nitrogen cycle by the compost itself. These observations have provided information on the qualitative indicators of compost in complex soil-plant interactions and offer a new perspective for chemically independent sustainable agriculture through the efficient use of natural nitrogen.

Objective: Among patients with atrial fibrillation, the risks of ischaemic stroke and systemic embolism (IS/SE) are high even with effective anticoagulation. Using large-scale, real-world data from Japan, this study aims to clarify residual risks of IS/SE attributable to modifiable risk factors among patients with atrial fibrillation who are taking oral anticoagulants.Methods: The study design we employed was a retrospective cohort. Health check-ups and insurance claims data of Japanese health insurance companies were accumulated from January 2005 to June 2017. We identified 11 848 participants with atrial fibrillation who were on oral anticoagulants during the study period. We set the modifiable risk factors as hypertension, diabetes and dyslipidaemia. A Cox proportional hazards model was used to obtain the effects of the risk factors for IS/SE.Results: During an average of 3 years' follow-up, 200 cases of IS/SE occurred (incidence rate 0.57 per 100 person-years). In multivariable analyses, older age (65-74 vs <65 years; adjusted HR 2.02 (95% CI 1.49 to 2.73)), hypertension (adjusted HR 1.41 (1.04 to 1.92)) and dyslipidaemia (adjusted HR 1.46 (1.07 to 1.98)) were significantly associated with increased risk of IS/SE. Percentage of IS/SE risk attributable to modifiable risk factors (hypertension, diabetes and dyslipidaemia) was 30.0% (16.1% to 41.6%).Conclusion: Among patients with atrial fibrillation on anticoagulant therapy, approximately one-third of the residual risks were estimated to be attributable to modifiable risk factors such as hypertension, diabetes and dyslipidaemia. [ABSTRACT FROM AUTHOR]

Anxiety is a symptom of various mental disorders, including depression. Severe anxiety can significantly affect the quality of life. Hesperidin (Hes), a flavonoid found in the peel of citrus fruits, reportedly has various functional properties, one of which is its ability to relieve acute and chronic stress. However, Hes is insoluble in water, resulting in a low absorption rate in the body and low bioavailability. Glucosyl hesperidin (GHes) is produced by adding one glucose molecule to hesperidin. Its water solubility is significantly higher than that of Hes, which is expected to improve its absorption into the body and enhance its effects. However, its efficacy in alleviating anxiety has not yet been investigated. Therefore, in this study, the anxiolytic effects of GHes were examined in a zebrafish model of anxiety. Long-term administration of diets supplemented with GHes did not cause any toxicity in the zebrafish. In the novel tank test, zebrafish in the control condition exhibited an anxious behavior called freezing, which was significantly suppressed in GHes-fed zebrafish. In the black-white preference test, which also induces visual stress, GHes-fed zebrafish showed significantly increased swimming time in the white side area. Furthermore, in tactile (low water-level stress) and olfactory-mediated stress (alarm substance administration test) tests, GHes suppressed anxious behavior, and these effects were stronger than those of Hes. Increased noradrenaline levels in the brain generally cause freezing; however, in zebrafish treated with GHes, the amount of noradrenaline after stress was lower than that in the control group. Activation of c-fos/ERK/Th, which is upstream of the noradrenaline synthesis pathway, was also suppressed, while activation of the CREB/BDNF system, which is vital for neuroprotective effects, was significantly increased. These results indicate that GHes has a more potent anxiolytic effect than Hes in vivo, which may have potential applications in drug discovery and functional food development.

Ninjinyoeito, Hochuekkito, and Juzentaihoto are the three types of Kampo-hozai used to support the treatment of various diseases by energizing patients through improved mental health. While Kampo-hozais are clinically used to improve mental energy decline, a comparison between their effects on neuropsychiatric symptoms like anxiety and sociability and the strength of their effects has not been conducted. Therefore, this study compared the effects of Ninjinyoeito, Hochuekkito, and Juzentaihoto on psychiatric symptoms using neuropeptide Y knockout (NPY-KO) zebrafish, a suitable animal model for anxiety and low sociability. Neuropeptide Y knockout zebrafish were fed a Ninjinyoeito, Hochuekkito, or Juzentaihoto-supplemented diet for 4 days. Then, sociability was analyzed using a three-Chambers test and anxiety-like behavior was evaluated using the cold stress and novel tank tests. The results showed that Ninjinyoeito treatment improved the low sociability of neuropeptide Y knockout, while Hochuekkito and Juzentaihoto did not. Neuropeptide Y knockout exhibited anxiety-like behaviors, such as freezing and swimming in the wall area under cold stress, but Ninjinyoeito treatment improved these behaviors. However, these anxiety-like behaviors were not improved by Hochuekkito and Juzentaihoto. Ninjinyoeito treatment also improved anxiety-like behaviors of neuropeptide Y knockout in the novel tank test. However, no improvement was shown in the Hochuekkito and Juzentaihoto groups. This trend was also confirmed in the low water stress test using wild-type zebrafish. This study exhibits that among the three types of Kampo-hozai, Ninjinyoeito is the most effective in psychiatric disorders associated with anxiety and low sociability.

Sociability is an essential component of the linkage structure in human and other vertebrate communication. Low sociability is defined as a poor social approach, including social withdrawal and apathy, and is implicated in a variety of psychiatric disorders. Ninjinyoeito (NYT), a traditional Japanese herbal medicine, has been used in the medical field. This study aimed to determine the effect of NYT on low sociality in NPY-KO zebrafish. NPY-KO zebrafish were fed a 3% NYT-supplemented diet for 4 days and subjected to behavioral tests. In the mirror test, NPY-KO zebrafish fed a control diet showed avoidance behavior toward their mirror counterparts. In contrast, the treatment of NPY-KO zebrafish with NYT significantly increased their interaction with their counterparts in the mirror. In addition, a 3-chambers test was conducted to confirm the effect of NYT on the low sociality of NPY-KO zebrafish. NPY-KO zebrafish fed the control diet showed less interaction with fish chambers, while NYT treatment increased the interaction. Phosphorylation of ERK, a marker of neuronal activity, was significantly reduced in the whole brain of NYT-fed NPY-KO zebrafish, compared to the control diet. NYT treatment significantly suppressed hypothalamic-pituitary-adrenal-related genes (gr, pomc, and crh) and sympathetic-adrenal-medullary-related genes (th1, th2, and cck) in NPY-KO zebrafish. NYT administration significantly reduced mRNA levels of gad1b compared to the control diet, suggesting the involvement of GABAergic neurons in NYT-induced improvement of low sociability. Furthermore, the expression of CREB was suppressed when NPY-KO zebrafish were fed NYT. Next, we attempted to identify the effective herb responsible for the NYT-induced improvement of low sociability. NPY-KO zebrafish were fed an experimental diet containing the target herb for 4 days, and its effect on sociability was evaluated using the 3-chambers test. Results showed that Cinnamon Bark and Polygala Root treatments significantly increased time spent in the fish tank area compared to the control diet, while the other 10 herbs did not. We confirmed that these two herbs suppressed the activity of HPA-, SAM-, and GABAergic neurons, as well as NYT-treated zebrafish, accompanied by downregulation of CREB signaling. This study suggests the potential use of NYT as a drug for sociability disorders.

Millimeter-wave irradiation of wheat seeds enhances the growth of roots under flooding stress, but its mechanism is not clearly understood. To understand the role of millimeter-wave irradiation on root-growth enhancement, membrane proteomics was performed. Membrane fractions purified from wheat roots were evaluated for purity. H+-ATPase and calnexin, which are protein markers for membrane-purification efficiency, were enriched in a membrane fraction. A principal-component analysis of the proteomic results indicated that the millimeter-wave irradiation of seeds affects membrane proteins in grown roots. Proteins identified using proteomic analysis were confirmed using immunoblot or polymerase chain reaction analyses. The abundance of cellulose synthetase, which is a plasma-membrane protein, decreased under flooding stress; however, it increased with millimeter-wave irradiation. On the other hand, the abundance of calnexin and V-ATPase, which are proteins in the endoplasmic reticulum and vacuolar, increased under flooding stress; however, it decreased with millimeter-wave irradiation. Furthermore, NADH dehydrogenase, which is found in mitochondria membranes, was upregulated due to flooding stress but downregulated following millimeter-wave irradiation even under flooding stress. The ATP content showed a similar trend toward change in NADH dehydrogenase expression. These results suggest that millimeter-wave irradiation improves the root growth of wheat via the transitions of proteins in the plasma membrane, endoplasmic reticulum, vacuolar, and mitochondria.

Electronic states in solid-solution transition metal oxides may differ from those in their parent compounds, and this results in interesting electronic properties. In this study, the valence states and electronic properties of solid solutions of (1 − x)PbVO3− xBiCrO3 are reported. The solid solutions are successfully synthesized under high-pressure and high-temperature conditions of 5 GPa or 7 GPa and 1273 K, respectively. A change in the crystal structure from centrosymmetric monoclinic (C2/c), as in BiCrO3, to polar tetragonal (P4mm), as in PbVO3, is observed. A tetragonal-to-cubic phase transition, which results in a negative thermal expansion, was observed in 7/8PbVO3-1/8BiCrO3 at approximately 700 K. X-ray absorption spectroscopy and magnetic studies reveal that the Cr and V atoms are in the valence states 3+ and 4+, respectively, which are the same as those of the parent compounds. Thus, it was concluded that the valence state of V4+/Cr3+ and the electron localization in the (1 − x)PbVO3− xBiCrO3 solid solutions are considerably robust.

PbFeO3 is part of a family of lead based perovskites with many intriguing properties; however, difficulties in synthesis have hampered investigation. Here, the authors present a detailed study of the structure of PbFeO3 observing unique charge ordering and spin orientation among the constituent ions.

Abstract Examining intestine–liver interactions is important for achieving the desired physiological drug absorption and metabolism response in in vitro drug tests. Multi-organ microphysiological systems (MPSs) constitute promising tools for evaluating inter-organ interactions in vitro. For coculture on MPSs, normal cells are challenging to use because they require complex maintenance and careful handling. Herein, we demonstrated the potential of coculturing normal cells on MPSs in the evaluation of intestine–liver interactions. To this end, we cocultured human-induced pluripotent stem cell-derived intestinal cells and fresh human hepatocytes which were isolated from PXB mice with medium circulation in a pneumatic-pressure-driven MPS with pipette-friendly liquid-handling options. The cytochrome activity, albumin production, and liver-specific gene expressions in human hepatocytes freshly isolated from a PXB mouse were significantly upregulated via coculture with hiPS-intestinal cells. Our normal cell coculture shows the effects of the interactions between the intestine and liver that may occur in vivo. This study is the first to demonstrate the coculturing of hiPS-intestinal cells and fresh human hepatocytes on an MPS for examining pure inter-organ interactions. Normal-cell coculture using the multi-organ MPS could be pursued to explore unknown physiological mechanisms of inter-organ interactions in vitro and investigate the physiological response of new drugs.

Abstract Nonhost resistance of Arabidopsis thaliana against the hemibiotrophic fungus Colletotrichum tropicale requires PEN2-dependent preinvasive resistance and CYP71A12 and CYP71A13-dependent postinvasive resistance, which both rely on tryptophan (Trp) metabolism. We here revealed that CYP71A12, CYP71A13 and PAD3 are critical for Arabidopsis’ postinvasive basal resistance toward the necrotrophic Alternaria brassicicola. Consistent with this, gene expression and metabolite analyses suggested that the invasion by A. brassicicola triggered the CYP71A12-dependent production of indole-3-carboxylic acid derivatives and the PAD3 and CYP71A13-dependent production of camalexin. We next addressed the activation of the CYP71A12 and PAD3-dependent postinvasive resistance. We found that bak1-5 mutation significantly reduced postinvasive resistance against A. brassicicola, indicating that pattern recognition contributes to activation of this second defense-layer. However, the bak1-5 mutation had no detectable effects on the Trp-metabolism triggered by the fungal penetration. Together with this, further comparative gene expression analyses suggested that pathogen invasion in Arabidopsis activates (1) CYP71A12 and PAD3-related antifungal metabolism that is not hampered by bak1-5, and (2) a bak1-5 sensitive immune pathway that activates the expression of antimicrobial proteins.

Objective: To examine the impact of inter-provider care coordination on health-care resource utilization among elderly acute stroke patients.Design: A retrospective cohort study using health-care insurance claims data.Setting: Claims data of the Fukuoka Prefecture Wide-Area Association of Latter-Stage Elderly Healthcare.Participants: About, 6409 patients aged 75 years or older admitted for acute stroke and moved to rehabilitation wards from 1 April 2010 to 30 September 2015.Main Outcome Measure: Lengths of stay (LOS) and total charge (TC) were evaluated according to three groups of care pathways (coordinated care, integrated care and other pathways).Results: Compared with the other care pathway, the coordinated care groups had significantly shorter LOS of 2.0 days in acute ischemic stroke care; they had 2.5 days shorter LOS in hemorrhagic stroke care. However, there were no significant differences in rehabilitation care LOS and TC.Conclusions: Our findings suggest that a payment system for care coordination is inappropriate since it was not associated with a reduction in overall health-care resource utilization. Further, health-care system reform is necessary to improve care continuity across multiple health-care institutions in Japan. [ABSTRACT FROM AUTHOR]

The plant epidermis is the first line of plant defense against pathogen invasion, and likely contains important regulatory proteins related to the plant–pathogen interaction. This study aims to identify the candidates of these regulatory proteins expressed in the plant epidermis. We performed comparative proteomic studies to identify rapidly and locally expressed proteins in the leaf epidermis inoculated with fungal phytopathogen. The conidia solutions were dropped onto the Arabidopsis leaf surface, and then, we collected the epidermal tissues from inoculated and mock-treated leaves at 4 and 24 hpi. The label-free quantification methods showed that expressions of Arabidopsis proteins, which are related to defense signals, such as BAK1, MKK5, receptor-like protein kinases, transcription factors, and stomatal functions, were rapidly induced in the epidermal tissues of inoculated leaves. In contrast, most of them were not differentially regulated by fugal inoculation in the whole leaves. These findings clearly indicate that epidermal proteomics can monitor locally expressed proteins in inoculated areas of plant tissues. We also identified the 61 fungal proteins, including effector-like proteins specifically expressed on the Arabidopsis epidermis. Our new findings suggested that epidermal proteomics is useful for understanding the local expressions of plant and fungal proteins related to their interactions.

Few studies have evaluated the effects of lifestyle habits, such as eating behaviors, on the development of nonalcoholic fatty liver disease (NAFLD). It is known that NAFLD increases the risk of type 2 diabetes, prediabetes, cardiovascular disease, and chronic kidney disease. Therefore, a retrospective cohort study was conducted to evaluate the effect of eating behaviors and interactions between these behaviors on the development of NAFLD among health insurance beneficiaries without NAFLD. Study subjects were 2254 male and female insurance beneficiaries without NAFLD who had attended specific health checkups during fiscal years 2009 and 2012 among health insurance societies located in Fukuoka and Shizuoka Prefectures (Japan). The incidence of NAFLD was defined as Fatty Liver Index scores ≥60 or visiting medical organizations for fatty liver disease treatment according to claims data. Eating behaviors, including eating speed and eating before bedtime, were evaluated by a self-administered questionnaire. During the study period, 52 (2.3%) subjects progressed to NAFLD. Subjects who ate before bedtime but did not eat fast had a higher risk of NAFLD (adjusted odds ratio [AOR] = 2.15; 95% confidence interval [CI]: 1.03-4.46). Those with both negative eating habits had a significantly higher risk of NAFLD (AOR = 2.48; 95% CI: 1.09-5.63). Subjects who habitually ate before bedtime, and those who ate fast and before bedtime, tended to have an increased risk of NAFLD. Earlier intervention to modify these poor eating behaviors could be useful to prevent NAFLD. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to quantify the effects of diabetes with pharmacotherapy-treated breast cancer on care resource use.Materials and Methods: The study was designed as a single institutional retrospective cohort study using hospital administrative data. The subjects were 152 patients admitted to a hospital from 2008 to 2012 diagnosed with breast cancer, and who underwent pharmacotherapy. We identified diabetes group and nondiabetes group in addition to other variables and quantified the effects of diabetes with breast cancer patients undergoing pharmacotherapy on care resource use, using a multilevel linear regression model.Results: Diabetes was significantly correlated to both longer length of stay (coefficient standard error: 0.75 [0.19], P < 0.001) and higher total hospital charge (0.72 [0.18], P < 0.001), controlled for age, pharmacotherapeutic agent, steroid use, admission route, procedures, and postpharmacotherapy events.Conclusion: This study showed that diabetes itself is a risk factor for greater care resource use after controlling for confounding factors. Pharmacotherapy for breast cancer may influence poor glycemic control, thus leading to greater care resource use. Early detection and careful monitoring of diabetes are essential in malignancy to eliminate this burden on the health care system. [ABSTRACT FROM AUTHOR]

Superfolds are folds commonly observed among evolutionarily unrelated multiple superfamilies of proteins. Since discovering superfolds almost two decades ago, structural rules distinguishing superfolds from the other ordinary folds have been explored but remained elusive. Here, we analyzed a typical superfold, the ferredoxin fold, and the fold which reverses the N to C terminus direction from the ferredoxin fold as a case study to find the rule to distinguish superfolds from the other folds. Though all the known structural characteristics for superfolds apply to both the ferredoxin fold and the reverse ferredoxin fold, the reverse fold has been found only in a single superfamily. The database analyses in the present study revealed the structural preferences of αβ- and βα-units; the preferences separate two α-helices in the ferredoxin fold, preventing their collision and stabilizing the fold. In contrast, in the reverse ferredoxin fold, the preferences bring two helices near each other, inducing structural conflict. The Rosetta folding simulations suggested that the ferredoxin fold is physically much more realizable than the reverse ferredoxin fold. Therefore, we propose that minimal structural conflict or minimal frustration among secondary structures is the rule to distinguish a superfold from ordinary folds. Intriguingly, the database analyses revealed that a most stringent structural rule in proteins, the right-handedness of the βαβ-unit, is broken in a set of structures to prevent the frustration, suggesting the proposed rule of minimum frustration among secondary structural units is comparably strong as the right-handedness rule of the βαβ-unit.

Background: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. Reninangiotensin system (RAS) inhibitors are the first-line treatment for diabetic patients with hypertension. However, whether RAS inhibitors prevent the development of DKD remains controversial. We conducted a retrospective cohort study quantifying the preventive effect of antihypertensive treatment with RAS inhibitors on DKD, using data from specific health check-ups and health insurance claims. Methods: The study subjects were 418 patients with diabetes and hypertension, drawn from health insurance societies located in Fukuoka and Shizuoka prefectures in Japan. The subjects were divided into three groups, according to the type of antihypertensive treatment they received. They were then compared in terms of the development of DKD, using the diagnostic codes from ICD-10. Results: Thirty subjects (6.2%) developed DKD during the study period between April 2011 and September 2013. RAS inhibitor treated group showed a significantly lower risk of DKD [adjusted odds ratio (AOR) = 0.35; 95% confidential interval (CI): 0.16-0.76] compared with the no treatment group. Conclusion: We conclude that antihypertensive treatment with RAS inhibitors is potentially useful for preventing the development of DKD. [ABSTRACT FROM AUTHOR]

KAGRA is a gravitational-wave (GW) detector constructed in Japan with two unique key features: It was constructed underground, and the test-mass mirrors are cooled to cryogenic temperatures. These features are not included in other kilometer-scale detectors but will be adopted in future detectors such as the Einstein Telescope. KAGRA performed its first joint observation run with GEO600 in 2020. In this observation, the sensitivity of KAGRA to GWs was inferior to that of other kilometer-scale detectors such as LIGO and Virgo. However, further upgrades to the detector are ongoing to reach the sensitivity for detecting GWs in the next observation run, which is scheduled for 2022. In this article, the current situation, sensitivity, and future perspectives are reviewed.

Background: Japan has a high prevalence of adult T-cell leukaemia (ATL), especially in the Kyushu/Okinawa region. Regional differences in prevalence might cause regional differences in physicians' experiences and the efficiency of care-resource use. This study investigated regional differences in the performance of bone marrow transplantation (BMT), outcome and care-resource use in patients with ATL in Japan. Methods: This was a cross-sectional study using a Japanese hospital administrative database in 2010, with a diagnostic-procedure combination/per diem payment system. We examined the association between BMT performance, resource use, outcomes and region. Results: We analysed data for 712 subjects of whom 60.5% were Kyushu/Okinawa residents. Significantly more patients with ATL underwent BMT in Kanto (p = 0.018) and Kansai (p < 0.001) regions compared with the Kyushu/Okinawa regions. The lengths of hospital stay were longer in Kanto (p = 0.002) and Kansai (p = 0.006) regions than in the Kyushu/Okinawa region. Total health-care costs were higher in Kanto (p = 0.001) and Kansai (p = 0.005) regions than the Kyushu/Okinawa region. The risks of in hospital mortality were not significantly different between regions. Conclusions: There were significant regional differences in BMT performance and resource use within Japan. ATL prevalence was not related to the performance of BMTs, resource use or outcomes. Factors related to regional socioeconomics might affect the performance of BMTs and care resource use within Japan. [ABSTRACT FROM AUTHOR]

Pseudomonas entomophila is a highly pathogenic bacterium that infects insects. It is also used as a suitable model pathogen to analyze Drosophila's innate immunity. P. entomophila's virulence is largely derived from Monalysin, a β-barrel pore-forming toxin that damages Drosophila tissues, inducing necrotic cell death. Here we report the first and efficient purification of endogenous Monalysin and its characterization. Monalysin is successfully purified as a pro-form, and trypsin treatment results in a cleaved mature form of purified Monalysin which kills Drosophila cell lines and adult flies. Electrophysiological measurement of Monalysin in a lipid membrane with an on-chip device confirms that Monalysin forms a pore, in a cleavage-dependent manner. This analysis also provides a pore-size estimate of Monalysin using current amplitude for a single pore and suggests lipid preferences for the insertion. Atomic Force Microscope (AFM) analysis displays its structure in a solution and shows that active-Monalysin is stable and composed of an 8-mer complex; this observation is consistent with mass spectrometry data. AFM analysis also shows the 8-mer structure of active-Monalysin in a lipid bilayer, and real-time imaging demonstrates the moment at which Monalysin is inserted into the lipid membrane. These results collectively suggest that endogenous Monalysin is indeed a pore-forming toxin composed of a rigid structure before pore formation in the lipid membrane. The endogenous Monalysin characterized in this study could be a desirable tool for analyzing host defense mechanisms against entomopathogenic bacteria producing damage-inducing toxins.

Plant-derived smoke solution enhances soybean root growth; however, its mechanism is not clearly understood. Subcellular proteomics techniques were used for underlying roles of plant-derived smoke solution on soybean root growth. The fractions of membrane and nucleus were purified and evaluated for purity. ATPase and histone were enriched in the fractions of membrane and nucleus, respectively. Principal component analysis of proteomic results indicated that the plant-derived smoke solution affected the proteins in the membrane and nucleus. The proteins in the membrane and nucleus mainly increased and decreased, respectively, by the treatment of plant-derived smoke solution compared with control. In the proteins in the plasma membrane, ATPase increased, which was confirmed by immunoblot analysis, and ATP contents increased through the treatment of plant-derived smoke solution. Additionally, although the nuclear proteins mainly decreased, the expression of RNA polymerase II was up-regulated through the treatment of plant-derived smoke solution. These results indicate that plant-derived smoke solution enhanced soybean root growth through the transcriptional promotion with RNA polymerase II expression and the energy production with ATPase accumulation.

Abstract Nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD), is known to act as a functional molecule in animals, whereas its function in plants is largely unknown. In this study, we found that NMN accumulated in barley cultivars resistant to phytopathogenic fungal Fusarium species. Although NMN does not possess antifungal activity, pretreatment with NMN and related metabolites enhanced disease resistance to Fusarium graminearum in Arabidopsis leaves and flowers and in barley spikes. The NMN-induced Fusarium resistance was accompanied by activation of the salicylic acid-mediated signalling pathway and repression of the jasmonic acid/ethylene-dependent signalling pathways in Arabidopsis. Since NMN-induced disease resistance was also observed in the SA-deficient sid2 mutant, an SA-independent signalling pathway also regulated the enhanced resistance induced by NMN. Compared with NMN, NAD and NADP, nicotinamide pretreatment had minor effects on resistance to F. graminearum. Constitutive expression of the NMNAT gene, which encodes a rate-limiting enzyme for NAD biosynthesis, resulted in enhanced disease resistance in Arabidopsis. Thus, modifying the content of NAD-related metabolites can be used to optimize the defence signalling pathways activated in response to F. graminearum and facilitates the control of disease injury and mycotoxin accumulation in plants.

Carbon nitride has noteworthy properties including high hardness levels. If the c-C3N4 or β-C3N4 structure can be synthesized, then hardness levels higher than that of diamond can be obtained. It is important to clarify the effect of ion impact on the growth of crystalline carbon nitrides on the synthesis of super-hard carbon nitrides. The ion beam-assisted deposition (IBAD) technique provides independent control over parameters, such as ion energy, temperature, and arrival rate of the atomic species during deposition. In this study, we investigated the structure and composition of a carbon nitride film prepared using graphitic carbon nitride as the evaporation source for the IBAD. The graphitic carbon nitride was formed into a pellet by press molding. The film deposited without nitrogen ion beam was obtained by evaporation using the pellet molded at 200 °C and 300 °C as the evaporation source. An amorphous carbon nitride film was obtained by IBAD using g-C3N4 as the evaporation source. The main chemical bonding in the carbon nitride film changed from C-N=C to C-C by varying the acceleration voltage of the nitrogen ion beam. Accordingly, the hardness of the film was increased. The hardness of the film at an acceleration voltage of 500 V was 23 GPa. This is due to the breaking of the CN bond by the ion beam, depending on the acceleration voltage of the ion beam.

Nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD), induces disease resistance to the Fusarium head blight fungus Fusarium graminearum in Arabidopsis and barley, but it is unknown at which stage of the infection it acts. Since the rate of haustorial formation of an obligate biotrophic barley powdery mildew fungus Blumeria graminis f. sp. hordei (Bgh) was significantly reduced in NMN-treated coleoptile epidermal cells, the possibility that NMN induces resistance to the biotrophic stage of F. graminearum was investigated. The results show that NMN treatment caused the wandering of hyphal growth and suppressed the formation of appressoria-like structures. Furthermore, we developed an experimental system to monitor the early stage of infection in real-time and analyzed the infection behavior. We observed that the hyphae elongated windingly by NMN treatment. These results suggest that NMN potentiates resistance to the biotrophic invasion of F. graminearum as well as Bgh.

Pyridine nucleotides such as a nicotinamide adenine dinucleotide (NAD) are known as plant defense activators. We previously reported that nicotinamide mononucleotide (NMN) enhanced disease resistance against fungal pathogen Fusarium graminearum in barley and Arabidopsis. In this study, we reveal that the pretreatment of nicotinamide (NIM), which does not contain nucleotides, effectively suppresses disease development of Fusarium Head Blight (FHB) in wheat plants. Correspondingly, deoxynivalenol (DON) mycotoxin accumulation was also significantly decreased by NIM pretreatment. A metabolome analysis showed that several antioxidant and antifungal compounds such as trigonelline were significantly accumulated in the NIM-pretreated spikes after inoculation of F. graminearum. In addition, some metabolites involved in the DNA hypomethylation were accumulated in the NIM-pretreated spikes. On the other hand, fungal metabolites DON and ergosterol peroxide were significantly reduced by the NIM pretreatment. Since NIM is relative stable and inexpensive compared with NMN and NAD, it may be more useful for the control of symptoms of FHB and DON accumulation in wheat and other crops.

The hemibiotrophic fungus Colletotrichum orbiculare first establishes a biotrophic infection stage in cucumber (Cucumber sativus) epidermal cells and subsequently transitions to a necrotrophic stage. Here, we found that C. orbiculare established hemibiotrophic infection via C. orbiculare WHI2, a yeast stress regulator homolog, and TOR (target of rapamycin) signaling. Plant defense responses such as callose deposition, H2O2, and antimicrobial proteins were strongly induced by the C. orbiculare whi2Δ mutant, resulting in defective pathogenesis. Expression analysis of biotrophy-specific genes evaluated by the promoter VENUS fusion gene indicated weaker VENUS signal intensity in the whi2Δ mutant, thereby suggesting that C. orbiculare WHI2 plays a key role in regulating biotrophic infection of C. orbiculare. The involvement of CoWHI2 in biotrophic infection was further explored with a DNA microarray. In the Cowhi2Δ mutant, TOR-dependent ribosomal protein–related genes were strikingly upregulated compared with the wild type. Moreover, callose deposition in the host plant after inoculation with the Cowhi2Δ mutant treated with rapamycin, which inhibits TOR activity, was reduced, and the mutant remained biotrophic in contrast to the untreated mutant. Thus, regulation of TOR by Whi2 is apparently crucial to the biotrophic stage of hemibiotrophic infection in C. orbiculare.

Extensive utilization of silver nanoparticles (NPs) in agricultural products results in their interaction with other chemicals in the environment. To study the combined effects of silver NPs with nicotinic acid and potassium nitrate (KNO3), a gel-free/label-free proteomic technique was used. Root length/weight and hypocotyl length/weight of soybean were enhanced by silver NPs mixed with nicotinic acid and KNO3. Out of a total 6340 identified proteins, 351 proteins were significantly changed, out of which 247 and 104 proteins increased and decreased, respectively. Differentially changed proteins were predominantly associated with protein degradation and synthesis according to the functional categorization. Protein-degradation-related proteins mainly consisted of the proteasome degradation pathway. The cell death was significantly higher in the root tips of soybean under the combined treatment compared to flooding stress. Accumulation of calnexin/calreticulin and glycoproteins was significantly increased under flooding with silver NPs, nicotinic acid, and KNO3. Growth of soybean seedlings with silver NPs, nicotinic acid, and KNO3 was improved under flooding stress. These results suggest that the combined mixture of silver NPs, nicotinic acid, and KNO3 causes positive effects on soybean seedling by regulating the protein quality control for the mis-folded proteins in the endoplasmic reticulum. Therefore, it might improve the growth of soybean under flooding stress.

Idiopathic pulmonary fibrosis is a devastating disease with poor prognosis. The pathogenic role of the lysophospholipid mediator sphingosine-1-phosphate and its receptor S1PR2 in lung fibrosis is unknown. We show here that genetic deletion of S1pr2 strikingly attenuated lung fibrosis induced by repeated injections of bleomycin in mice. We observed by using S1pr2LacZ/+ mice that S1PR2 was expressed in alveolar macrophages, vascular endothelial cells and alveolar epithelial cells in the lung and that S1PR2-expressing cells accumulated in the fibrotic legions. Bone marrow chimera experiments suggested that S1PR2 in bone marrow-derived cells contributes to the development of lung fibrosis. Depletion of macrophages greatly attenuated lung fibrosis. Bleomycin administration stimulated the mRNA expression of the profibrotic cytokines IL-13 and IL-4 and the M2 markers including arginase 1, Fizz1/Retnla, Ccl17 and Ccl24 in cells collected from broncho-alveolar lavage fluids (BALF), and S1pr2 deletion markedly diminished the stimulated expression of these genes. BALF cells from bleomycin-administered wild-type mice showed a marked increase in phosphorylation of STAT6, a transcription factor which is activated downstream of IL-13, compared with saline-administered wild-type mice. Interestingly, in bleomycin-administered S1pr2-/- mice, STAT6 phosphorylation in BALF cells was substantially diminished compared with wild-type mice. Finally, pharmacological S1PR2 blockade in S1pr2+/+ mice alleviated bleomycin-induced lung fibrosis. Thus, S1PR2 facilitates lung fibrosis through the mechanisms involving augmentation of IL-13 expression and its signaling in BALF cells, and represents a novel target for treating lung fibrosis.