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Increased endoplasmic reticulum (ER) stress is strongly associated with the phenotypic switching of vascular smooth muscle cells (VSMCs) in atherosclerosis. Depletion of the ER CaTunicamycin was used to mimic ER stress in vitro. Tunicamycin-induced ER stress caused CaM to dissociate from the RyR and translocate to the nucleus, which stimulated phenotypic switching through the activation of MEF2 and KLF5. Dantrolene suppressed tunicamycin-induced apoptosis, ER stress (restoring ER CaWe observed that ER stress causes CaM translocation to the nucleus and drives the phenotypic switching of VSMCs. Thus, restoration of the binding affinity of CaM to RyR may be a therapeutic target for atherosclerosis.

Dantrolene is a ryanodine receptor blocker that is used clinically for treatment of malignant hyperthermia. This study was conducted using murine aortic vascular smooth muscle cells (MOVAS) and a mouse arterial injury model to investigate the inhibitory effect of dantrolene on smooth muscle cell proliferation and migration. We investigated whether dantrolene suppressed platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell proliferation and migration in vitro. The effect of dantrolene on smooth muscle phenotype was evaluated using immunostaining. In addition, smooth muscle cell proliferation and phenotype switching were tested by applying dantrolene around blood vessels using a mouse arterial injury model. Dantrolene inhibited PDGF-induced cell proliferation and migration of MOVAS. Dantrolene also inhibited the switch from contractile to synthetic phenotype both in vitro and in vivo. Dantrolene is effective at inhibiting vascular smooth muscle cell proliferation, migration, and neointimal formation following arterial injury in mice.

Advanced heat soak test (HST) technology, the ‘in-line continuous HST’ has been reported on the basis of experimental investigations and the T-T-T (time–temperature–transformation) relationship. The new HST technology is continuously carried out just after tempering (and heat strengthening) process. It was registered in ISO-20657 (2017). High temperature microscopy observations, high temperature x-ray diffractometry, differential thermal analysis, and micro-Raman spectrometry have been carried out in order to elucidate the α–β phase transformation of nickel sulphide in detail. The breakage ratio of in-line continuous HST is the same as that of conventional off-line HST or excellent. The ‘in-line continuous HST’ is already operating in a Japanese glass plant in order to produce tempered (and heat strengthened) sheet glass with high safety and reliability. The in-line continuous HST technology has the following benefits: (a) improvements of both productivity and reliability, (b) automatic inspection just after the tempering–quenching process, and (c) improvements to productive performance (many kinds products, heteromorphic products, and mass production). In this technical report, the advanced ‘in-line continuous HST’ technology which was standardised by several experimental investigations and analytical results will be shown in detail. The effective and efficient manufacturing technology of the tempered (and heat strengthened) sheet glass will be introduced.

In animals, the health effects of ingested cacao proteins are unknown because the proteins are difficult to extract and purify from cacao beans.This study aimed to develop an extraction and purification method for cacao proteins and reveal the effect of ingestion of cacao proteins on defecation and intestinal microbiota in mice.Three groups of mice were fed a control diet (AIN-93 G), a cacao lignin diet (AIN-93 G containing 1.22% cacao lignin), or a cacao protein and lignin diet (AIN-93 G containing 1.97% cacao proteins and 1.22% cacao lignin) by pair-feeding for 8 d. Feces were collected as 2 bulked samples from days 1 to 4 and days 5 to 8 on each diet. The collected feces were weighed and the intestinal microbiota was analyzed by next-generation sequencing-based 16S rRNA.A new extraction and purification method for cacao proteins has been developed, then found that the proteins are resistant to digestive enzymes. However, the cacao protein powder made by this method contained 34.9% of lignin in addition to 56.4% of proteins. Therefore, to reveal the effect by cacao proteins alone, the fecal weight and intestinal microbiota of mice fed the cacao protein and lignin diet were compared with those of mice fed the cacao lignin diet. The fecal weight of mice fed the cacao protein and lignin diet was significantly greater than of mice fed the cacao lignin diet. The relative abundance ofIngestion of indigestible cacao proteins promoted defecation and altered the intestinal microbiota such as

Construction of regional inclusive care system is being promoted and pharmacists are required to implement multidisciplinary collaboration in order to provide appropriate pharmaceutical care to patients. However, there are few studies on collaboration between medical facilities and community pharmacies. In this study, we conducted a questionnaire survey of community pharmacies in Gifu City, which assessed the experience and attitudes regarding collaboration with other medical facilities. The survey items are: I. Participation in regional care meetings, II. Case discussion conferences, III. Joint workshops/study conferences, IV. Community service, V. Sharing information through medical cooperation network, and VI. Accompanying community pharmacists at home medical care. For the implementation of collaboration, the percentage of "not implemented" were as high as 70% or more in II, IV, V and VI. Regarding the attitudes toward collaboration, more than half of pharmacies answered that they wanted to implement in all items. In the comparison by the number of pharmacists, pharmacies with two or more pharmacists had significantly higher implementation ratios than pharmacies with one pharmacist in IV and V. Regarding the attitudes toward collaboration, pharmacies with two or more pharmacists had significantly higher ratios of considering implementation than pharmacies with one pharmacist in I and VI. Based on the results of this survey, there were many items that were not implemented as collaboration with other medical facilities at community pharmacies. However, many community pharmacies are planning to collaborate with other medical facilities in the future.

The consumption of health food products, such as Foods with Function Claims, has grown in Japan. Significant information, such as possible side effects or drug interactions, are expected to be described on the packaging to help consumers to make an informed choice about products. In this study, we checked the items described on the packaging of Foods with Function Claims containing eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA), Salacinol/Fagomine/Neokotalanol, or Varyl-Tyrosine/Lactotripeptide. We found that the label information on the package have issues that need to be addressed; for example, the description about a warning for concomitant use with antithrombotic drugs was found in only 29.7% of EPA and/or DHA containing products (44 out of 148). Providing information for safe usage of products to consumers is pivotal. Therefore, improving product labeling, and further pharmaceutical support in case of taking health foods, should be considered.

In Japan, within the background of a progressively aging society, a community general support system is gradually being established. Under this system, community pharmacists are expected to expand their activities in local communities. Here, we surveyed the distribution of community pharmacists in Japan by using government statistics. We found that there are 153 towns/villages without community pharmacists, which is about six times the number of towns without physicians (26 towns/villages). The number of community pharmacists per 100000 population was correlated with the population of the municipality. There was a significant difference in the number of community pharmacists per 100000 population between depopulated and non-depopulated areas. A multiple regression analysis revealed that population, financial capability index, and number of physicians per 100000 population were positively associated with the number of community pharmacists per 100000 population in a given municipality. We hope that the survey provides useful information about future issues facing community pharmacy in a community general support system.

The "self-medication tax deduction" system began in Japan in January 2017, allowing people to encourage the use of OTC drugs. Package inserts contain important information for consumers regarding their use. In this study, we first checked whether the items, as required in the notifications of the Japanese Ministry of Health, Labour and Welfare, are described in the package inserts of cold remedies and analgesic antipyretics in OTC drugs. The descriptions of almost all packages checked in this study were based on the notifications, but those of a small number of them were not. Next, we examined the description of the items, unrequired in the notification, but worthy for proper use of drugs; e.g., the description of prohibition for use by "patients with severe hypertension" in case of ibuprofen-containing products, and the description was found in only seven of 180 products. Manufactures should make package inserts along with notifications, including the description for proper use of drugs.

Background: Medicine education in Japan was introduced to junior high schools in 2012. However, the effectiveness of existing education programs is limited. In order to develop more effective programs for high school students, the present study investigated the variables that directly influence medicine use behavior and the magnitude of their influence, using a Bayesian network analysis. Methods: A national cross-sectional survey was conducted in 2017. Eighty-three public high schools across Japan were randomly selected, and questionnaires were administered to 15–16 years old 10th grade students. The number of valid responses was 17,437 (effective response rate was 98.46%). Responses were analyzed to measure students’ behavior toward, attitudes regarding, and knowledge of medicines, and awareness of their prior medicine education. Results: Students’ “attitude score” and “awareness of a class” directly influenced their “behavior score.” The “score on attitude,” which had a large influence on “score on behavior,” was directly influenced by “score on knowledge of proper use” and “awareness of class.” Conclusion: The present study argues that acquiring knowledge of appropriate medicine use leads to the acquisition of favorable attitudes, which may result in behavioral change. Therefore, for medicine education, it is expected that incorporating content related to knowledge acquisition for changing attitudes will be important for promoting behavioral change.

Background In recent years, the popularity of LED lighting has rapidly increased, owing to its many advantages, including economic benefits. We examined the change in the quality of drugs during storage under LED and fluorescent lighting and found that some medicines exhibited a different degree of color change depending on the light source. The purpose of this study was to investigate the effects of different plastic storage bags on the color change over time when various medicines were stored under LED and fluorescent lighting conditions. Methods Photostability tests were conducted on several types of target drugs. Subsequently, subjective evaluation by ten evaluators and objective evaluation by image analysis software were carried out regarding color change. Results A similar change in color tone was observed after all types of illumination. Subjective evaluation by 10 evaluators revealed that “change in color tone” occurred in the order of bulb-color LED lighting < daylight-color LED lighting < fluorescent lighting, regardless of the type of plastic bags. A similar tendency was observed also in objective evaluation. In this study, it was considered that a brown light-shielding plastic bag was more effective than a normal plastic bag for the prevention of the color change of medicines stored under LED lighting. Conclusions The above results suggested that the most appropriate combination of plastic bag and light source for medicine storage was a brown light-shielding plastic bag and bulb-color LED lighting. Electronic supplementary material The online version of this article (10.1186/s40780-018-0108-0) contains supplementary material, which is available to authorized users.

A putative new member of the family Totiviridae was identified in arboreal ants (Camponotus nipponicus). The viral dsRNA consisted of 5,713 nt with two overlapping open reading frames (ORFs). ORF1 encodes a putative capsid protein. ORF2 encodes a viral RNA-dependent RNA polymerase (RdRp). ORF2 could be translated as a fusion protein with the ORF1 product through a -1 frameshift in the overlapping ORF1. Phylogenetic analysis based on the RdRp revealed that the virus from C. nipponicus is closely related to Camponotus yamaokai virus, a member of the family Totiviridae, from another ant species. The name Camponotus nipponicus virus (CNV) is proposed for the new virus.

One of the activities of placental extracts (PEs) is skin-whitening effect, but the physiological and genetic mechanism for this effect has not yet been clarified. Here, we focus on PE as a regulator of antioxidant enzyme genes. Porcine PE was prepared, and its activity was investigated in B16 melanoma cells. PE treatment decreased the melanin content of UV-irradiated B16 cells in a dose-dependent manner. PE directly reduced the enzyme activity of tyrosinase in a cell-free assay. In addition, PE treatment increased the gene expression of cytosolic superoxide dismutase (SOD-1), extracellular SOD (SOD-3) and catalase but did not affect the expression of tyrosinase. Moreover, PE protected the B16 cells from H2O2-induced cell death. Taken together, our data suggest that PEs could play a role not only as a suppressor of melanin synthesis but also as a regulator of antioxidant genes and might protect the skin against oxidative stress.

Background: Endothelial-mesenchymal transformation (EndMT) is essential for endocardial cushion formation during cardiac morphogenesis. We recently identified Tmem100 as an endothelial gene indispensable for vascular development. In this study, we further investigated its roles for EndMT during atrioventricular canal (AVC) cushion formation. Results: Tmem100 was expressed in AVC endocardial cells, and Tmem100 null embryos showed severe EndMT defect in the AVC cushions. While calcineurin-dependent suppression of vascular endothelial growth factor (VEGF) expression in the AVC myocardium is important for EndMT, significant up-regulation of Vegfa expression was observed in Tmem100 null heart. EndMT impaired in Tmem100 null AVC explants was partially but significantly restored by the expression of constitutively-active calcineurin A, suggesting dysregulation of myocardial calcineurin-VEGF signaling in Tmem100 null heart. Moreover, Tmem100 null endocardial cells in explant culture did not show EndMT in response to the treatment with myocardium-derived growth factors, transforming growth factor β2 and bone morphogenetic protein 2, indicating involvement of an additional endocardial-specific abnormality in the mechanism of EndMT defect. The lack of NFATc1 nuclear translocation in endocardial cells of Tmem100 null embryos suggests impairment of endocardial calcium signaling. Conclusions: The Tmem100 deficiency causes EndMT defect during AVC cushion formation possibly via disturbance of multiple calcium-related signaling events. Developmental Dynamics 244:31–42, 2015. © 2014 Wiley Periodicals, Inc.

Summary The Hairy-related transcription factor family of Notch- and ALK1-downstream transcriptional repressors, called Hrt/Hey/Hesr/Chf/Herp/Gridlock, has complementary and indispensable functions for vascular development. While mouse embryos null for either Hrt1/Hey1 or Hrt2/Hey2 did not show early vascular phenotypes, Hrt1/Hey1; Hrt2/Hey2 double null mice (H1ko/H2ko) showed embryonic lethality with severe impairment of vascular morphogenesis. It remained unclear, however, whether Hrt/Hey functions are required in endothelial cells or vascular smooth muscle cells. In this study, we demonstrate that mice with endothelial-specific deletion of Hrt2/Hey2 combined with global Hrt1/Hey1 deletion (H1ko/H2eko) show abnormal vascular morphogenesis and embryonic lethality. Their defects were characterized by the failure of vascular network formation in the yolk sac, abnormalities of embryonic vascular structures and impaired smooth muscle cell recruitment, and were virtually identical to the H1ko/H2ko phenotypes. Among signaling molecules implicated in vascular development, Robo4 expression was significantly increased and activation of Src family kinases was suppressed in endothelial cells of H1ko/H2eko embryos. The present study indicates an important role of Hrt1/Hey1 and Hrt2/Hey2 in endothelial cells during early vascular development, and further suggests involvement of Robo4 and Src family kinases in the mechanisms of embryonic vascular defects caused by the Hrt/Hey deficiency. genesis 52:897–906, 2014. © 2014 Wiley Periodicals, Inc.

A simple electrochemical scheme has been worked out to effectively concentrate Pt particles in a colloidal solution by application of a DC current of typically 40–80 V across the electrodes separated by 3 cm within 15 min. When the voltage was applied between the cathode and anode in the colloidal solution, the colloidal particles were separated horizontally into vacant and dense layers. The particles were finally concentrated below the bottom edge of the anode in the solution, and the boundary height of the vacant and dense layers was found to depend on the depth of the bottom edge of the anode.

Lawsonite, pumpellyite and epidote coexist in the chlorite zone pelitic schists of the Sanbagawa metamorphic belt. As these pelitic schists contain calcite ubiquitously, the phase relations of hydrous Ca-Al silicate minerals are examined by mixed volatile equilibria in the K2O-Na2O-CaO-MgO-Al2O3-SiO2-CO2-H2O system with excess quartz, calcite and a fluid phase. XCO2 of the stability field of pumpellyite is lower than that of lawsonite. An idealized geometry of an isobaric T-XCO2 diagram including mixed volatile reactions shows that the stable hydrous Ca-Al mineral changes from lawsonite through pumpellyite to epidote for pelitic schists in the chlorite zone with progressive increase in both temperature and XCO2 of the fluid phase, though ferric iron expands the stability of epidote throughout the chlorite zone. The fluid phase released by the metamorphic reactions in the chlorite zone is high in H2O content even in the presence of CaCO3. The proposed mixed volatile reactions, instead of the pure dehydration reactions, are applicable directly to the phase relations of CaCO3-bearing Sanbagawa basic schists and to the interpretation of the mineral sequence of the hydrous Ca-Al silicates of other high P/T metamorphic belts.

A novel dsRNA virus was identified from the arboreal ant Camponotus yamaokai. The complete nucleotide sequence analysis of the virus revealed that the virus consisted of 5704 bp with two ORFs. ORF1 (3084 nt) encoded a putative capsid protein. ORF2 (1977 nt) encoded a viral RNA-dependent RNA polymerase (RdRp). ORF2 could be translated as a fusion with the ORF1 product by a - 1 frameshift in the overlapping ORF1. Phylogenetic analyses based on the RdRp revealed that the virus from C. yamaokai was most likely a novel totivirus, but it was not closely related to the previously known totiviruses in arthropods. Transmission electron microscopy revealed isometric virus particles of ~30 nm diameter in the cytoplasm, which was consistent with the characteristics of the family Totiviridae. The virus was detected by reverse transcription-PCR in all caste members and developmental stages of ants, including eggs, larvae, pupae, adult workers, alates (male and female) and queens. To our knowledge, this is the first report of a member of the family Totiviridae in a hymenopteran; the virus was designated Camponotus yamaokai virus.

The frequency of occurrence of minerals in 1876 samples of Sanbagawa pelitic schist in central Shikoku is summarized on the basis of microscopic observation accompanied, in part, by use of an electron microprobe. All samples contain quartz, plagioclase, phengite, chlorite and graphite. More than 90% of samples contain clinozoisite, titanite and apatite. Garnet is present in 95% of samples from the garnet zone, and biotite is present in 64% of samples from the albite-biotite zone. Calcite is found in about 40% of samples of the pelitic schist collected from outcrop, but occurs in 95% of the pelitic schist from drill cores. Calcite was apparently ubiquitous in the pelitic schist during the Sanbagawa metamorphism, but must have been dissolved recently by the action of surface or ground water. The mineral assemblages of the Sanbagawa pelitic schist have to be analyzed in the system with excess calcite, quartz, albite (or oligoclase), clinozoisite, graphite and fluid that is composed mainly of H2O, CO2 and CH4. In the presence of calcite, reactions that produce garnet, rutile, oligoclase, biotite and hornblende, some of which define isograds of the metamorphic belt, should be written as mixed volatile equilibria that tend to take place at lower temperature than the dehydration reactions that have been proposed. The presence of calcite in pelitic schist suggests that fluid composition is a variable as important in determining mineral assemblages as pressure and temperature. Thus Ca-bearing phases must be taken into account to analyze the phase relations of calcite-bearing pelitic schist, even if CaO content of Sanbagawa pelitic schist is low. As calcite is a common phase, the mineral assemblages of the biotite zone pelitic schist may contravene the mineralogical phase rule and warrant further study.

Endothelial-mesenchymal transformation (EndMT) is essential for endocardial cushion formation during cardiac morphogenesis. We recently identified Tmem100 as an endothelial gene indispensable for vascular development. In this study, we further investigated its roles for EndMT during atrioventricular canal (AVC) cushion formation.Tmem100 was expressed in AVC endocardial cells, and Tmem100 null embryos showed severe EndMT defect in the AVC cushions. While calcineurin-dependent suppression of vascular endothelial growth factor (VEGF) expression in the AVC myocardium is important for EndMT, significant up-regulation of Vegfa expression was observed in Tmem100 null heart. EndMT impaired in Tmem100 null AVC explants was partially but significantly restored by the expression of constitutively-active calcineurin A, suggesting dysregulation of myocardial calcineurin-VEGF signaling in Tmem100 null heart. Moreover, Tmem100 null endocardial cells in explant culture did not show EndMT in response to the treatment with myocardium-derived growth factors, transforming growth factor β2 and bone morphogenetic protein 2, indicating involvement of an additional endocardial-specific abnormality in the mechanism of EndMT defect. The lack of NFATc1 nuclear translocation in endocardial cells of Tmem100 null embryos suggests impairment of endocardial calcium signaling.The Tmem100 deficiency causes EndMT defect during AVC cushion formation possibly via disturbance of multiple calcium-related signaling events.

The Hairy-related transcription factor family of Notch- and ALK1-downstream transcriptional repressors, called Hrt/Hey/Hesr/Chf/Herp/Gridlock, has complementary and indispensable functions for vascular development. While mouse embryos null for either Hrt1/Hey1 or Hrt2/Hey2 did not show early vascular phenotypes, Hrt1/Hey1; Hrt2/Hey2 double null mice (H1(ko) /H2(ko) ) showed embryonic lethality with severe impairment of vascular morphogenesis. It remained unclear, however, whether Hrt/Hey functions are required in endothelial cells or vascular smooth muscle cells. In this study, we demonstrate that mice with endothelial-specific deletion of Hrt2/Hey2 combined with global Hrt1/Hey1 deletion (H1(ko) /H2(eko) ) show abnormal vascular morphogenesis and embryonic lethality. Their defects were characterized by the failure of vascular network formation in the yolk sac, abnormalities of embryonic vascular structures and impaired smooth muscle cell recruitment, and were virtually identical to the H1(ko) /H2(ko) phenotypes. Among signaling molecules implicated in vascular development, Robo4 expression was significantly increased and activation of Src family kinases was suppressed in endothelial cells of H1(ko) /H2(eko) embryos. The present study indicates an important role of Hrt1/Hey1 and Hrt2/Hey2 in endothelial cells during early vascular development, and further suggests involvement of Robo4 and Src family kinases in the mechanisms of embryonic vascular defects caused by the Hrt/Hey deficiency.

The properties and origin of fine Na 2 SO 4 blisters have been studied experimentally. They are 0.1–1.0 mm in size and contain crystalline Na 2 SO 4 with a small amount of CaO and K 2 O. Most of them are formed in molten glass during decomposition of the batch mixture. The blisters are formed by condensation of Na 2 SO 4 from Na 2 O and SO 3 selectively absorbed into dolomite at an early stage of batch melting. They remain immiscibly in molten glass, after MgO and CaO in the dolomite have been dissolved into the glass.

In the northeastern part of the Kanto Mountains, central Japan, in basic schists, green biotite widely occurs in a lower-grade part where garnet is common in pelitic and psammitic schists, while brown biotite is present in a higher-grade part where brown biotite commonly occurs in them. Comparing with brown biotite from higher-grade part of the Sanbagawa metamorphic terrain in this area and central Shioku, green biotite in lower-grade part of this area contains lower Al2O3 and higher Fe2O3, and slightly lower TiO2. On the basis of the paragenetic relation of the green biotite-bearing assemblages, the occurrence of green biotite is explained by high Fe2O3, (FeO+MgO), and low Al2O3 contents of the host rocks. Brown biotite in basic schists in a higher-grade part is formed by the following reaction; green biotite+ (Fe, Mg-rich) chlorite+epidote+albite+quartz=brown bitite+hornblende+(Al-rich) chlorite+magnetite+H2O. This reaction enlarges the stability field of biotite, and in a higher-grade part, brown biotite-bearing assemblages widely occurs in the common basic schists.

Epidote, which contains significant amounts of rare earth elements and thorium, and allanite occur in the Sanbagawa pelitic schists of central Shikoku at all the metamorphic grades. Petrographical and chemical studies suggest a metamorphic origin of the REE-bearing epidote and a detrital origin of the allanite. The detrital allanite is the major source of REE and Th in the metamorphic epidote.

Most garnets in a small volume of the pelitic Sanbagawa schists nucleated simultaneously, grew, and then ceased with their growth, maintaining near-equilibrium with coexisting minerals such as chlorite and biotite during the prograde metamorphism. Chemical trends of zoned garnets systematically shift from the pyrope-poor to pyrope-rich portions in a ternary MnFeMg system in order of ascending metamorphic grade. A ternary (MnFeMg) model system suggests that the higher-grade garnets started to grow at lower pressures and higher temperatures than the lower-grade ones during prograde metamorphism. It follows that high-grade metamorphism took place at lower pressures in the garnet to oligoclase-biotite zones of the Sanbagawa metamorphic terrain in central Shikoku.

During the prograde metamorphism of the Sanbagawa metamorphic terrain in central Shikoku, garnet has grown in the pelitic schists whilst maintaining surface equilibrium with coexisting minerals such as chlorite and epidote, etc. In the quartz-albite layer, it has grown euhedrally. In the micaceous layer, its crystal morphology varies according to the different minerals in contact and their different orientations. Garnet enclosed in or sandwiched between micas is always ellipsoidal, extended parallel to the basal planes of the micas. However, when the edge of a garnet has intruded at an acute angle into the micas, euhedral garnet has grown. It is concluded that the growth of garnet at the interface with micas ceased when the {110} surface of garnet came into contact with the basal plane of the micas in the tectonic c -axis direction. Other models, such as chloritization-resorption, pressure-solution, and mechanical-erosion or grinding, do not adequately explain the origin of the flattened garnet. During retrograde metamorphism, chloritization and resorption of garnets took place in the matrix, resulting in the rough and irregular surface of garnet. Garnets included in albite porphyroblasts have been largely unaffected by the retrograde metamorphism.