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Cementum resorption, unlike bone resorption, is clinically known to occur only with limited pathological stimuli, such as trauma, orthodontic forces, and large apical periodontitis; however, the molecular mechanisms that control osteoclast formation on the cementum surface remain unclear. In this study, we focused on extracellular vesicles (EVs) secreted by cementoblasts and analyzed their effects on osteoclast differentiation. EVs were extracted from the conditioned medium (CM) of the mouse cementoblast cell line OCCM-30. Transmission electron microscopy (TEM) analysis confirmed the presence of EVs with a diameter of approximately 50–200 nm. The effect of the EVs on osteoclast differentiation was examined using the mouse osteoclast progenitor cell line RAW 264.7 with recombinant receptor activator of nuclear factor (NF)-κB ligand (rRANKL) stimulation. EVs enhanced the formation of tartrate-resistant acid phosphatase (TRAP) activity-positive cells upon rRANKL stimulation. EVs also enhanced the induction of osteoclast-associated gene and protein expression in this condition, as determined by real-time PCR and Western blotting, respectively. On the other hand, no enhancing effect of EVs was observed without rRANKL stimulation. A Western blot analysis revealed no expression of receptor activator of NF-κB ligand (RANKL) in EVs themselves. The effect on rRANKL-induced osteoclast differentiation was examined using the CM of cementoblasts in terms of TRAP activity-positive cell formation and osteoclast-associated gene expression. The conditioned medium partly inhibited rRANKL-induced osteoclast differentiation and almost completely suppressed its enhancing effect by EVs. These results indicate that cementoblasts secreted EVs, which enhanced RANKL-induced osteoclast differentiation, and simultaneously produced soluble factors that neutralized this enhancing effect of EVs, implicating this balance in the regulation of cementum absorption. A more detailed understanding of this crosstalk between cementoblasts and osteoclasts will contribute to the development of new therapies for pathological root resorption.

Pirfenidone is a first-line drug for the treatment of idiopathic pulmonary fibrosis. The primary metabolic pathways of pirfenidone in humans are 5-hydroxylation and subsequent oxidation to 5-carboxylpirfenidone. The aims of this study were to determine the cytochrome P450 isoforms responsible for pirfenidone 5-hydroxylation and to evaluate their contributions in human liver microsomes (HLM).Among the recombinant P450 isoforms, CYP1A2, CYP2D6, CYP2C19, CYP2A6, and CYP2B6 were shown to catalyse the 5-hydroxylation of pirfenidone. Pirfenidone 5-hydroxylase activity by HLM was inhibited by α-naphthoflavone (by 45%), 8-methoxypsolaren (by 84%), tranylcypromine (by 53%), and quinidine (by 15%), which are CYP1A2, CYP1A2/CYP2A6/CYP2C19, CYP2A6/CYP2C19, and CYP2D6 inhibitors, respectively.In 17 individual HLM donors, pirfenidone 5-hydroxylase activity was significantly correlated with phenacetin O-deethylase (r = 0.89, P

Aim Abiraterone acetate for metastatic castration-resistant prostate cancer is an acetylated prodrug to be hydrolyzed to abiraterone. Abiraterone acetate is known to be hydrolyzed by pancreatic cholesterol esterase secreted into the intestinal lumen. This study aimed to investigate the possibility that arylacetamide deacetylase (AADAC) expressed in enterocytes contributes to the hydrolysis of abiraterone acetate based on its substrate preference. Materials and methods Abiraterone acetate hydrolase activity was measured using human intestinal (HIM) and liver microsomes (HLM) as well as recombinant AADAC. Correlation analysis between activity and AADAC expression was performed in 14 individual HIMs. The in vivo pharmacokinetics of abiraterone acetate was examined using wild-type and Aadac knockout mice administered abiraterone acetate with or without orlistat, a pancreatic cholesterol esterase inhibitor. Key findings Recombinant AADAC showed abiraterone acetate hydrolase activity with similar Km value to HIM and HLM. The positive correlation between activity and AADAC levels in individual HIMs supported the responsibility of AADAC for abiraterone acetate hydrolysis. The area under the plasma concentration-time curve (AUC) of abiraterone after oral administration of abiraterone acetate in Aadac knockout mice was 38% lower than that in wild-type mice. The involvement of pancreatic cholesterol esterase in abiraterone formation was revealed by the decreased AUC of abiraterone by coadministration of orlistat. Orlistat potently inhibited AADAC, implying its potential as a perpetrator of drug-drug interactions. Significance AADAC is responsible for the hydrolysis of abiraterone acetate in the intestine and liver, suggesting that concomitant use of abiraterone acetate and drugs potently inhibiting AADAC should be avoided.

We investigate a quantum spatial search problem on fractal lattices, such as Sierpinski carpets and Menger sponges. In earlier numerical studies of the Sierpinski gasket, the Sierpinski tetrahedron, and the Sierpinski carpet, conjectures have been proposed for the scaling of a quantum spatial search problem finding a specific target, which is given in terms of the characteristic quantities of a fractal geometry. We find that our simulation results for extended Sierpinski carpets and Menger sponges support the conjecture for the ${\it optimal}$ number of the oracle calls, where the exponent is given by $1/2$ for $d_{\rm s} > 2$ and the inverse of the spectral dimension $d_{\rm s}$ for $d_{\rm s} < 2$. We also propose a scaling hypothesis for the ${\it effective}$ number of the oracle calls defined by the ratio of the ${\it optimal}$ number of oracle calls to a square root of the maximum finding probability. The form of the scaling hypothesis for extended Sierpinski carpets is very similar but slightly different from the earlier conjecture for the Sierpinski gasket, the Sierpinski tetrahedron, and the conventional Sierpinski carpet., 7 pages, 7 figures

Estradiol (E2) is locally synthesized within the hippocampus in addition to the gonads. Rapid modulation of hippocampal synaptic plasticity by E2 is essential for synaptic regulation. Molecular mechanisms of modulation through synaptic estrogen receptor (ER) and its downstream signaling, however, have been still unknown. We investigated induction of LTP by the presence of E2 upon weak theta burst stimulation (weak-TBS) in CA1 region of adult male hippocampus. Since only weak-TBS did not induce full-LTP, weak-TBS was sub-threshold stimulation. We observed LTP induction by the presence of E2, after incubation of hippocampal slices with 10 nM E2 for 30 min, upon weak-TBS. This E2-induced LTP was blocked by ICI, an ER antagonist. This E2-LTP induction was inhibited by blocking Erk MAPK, PKA, PKC, PI3K, NR2B and CaMKII, individually, suggesting that Erk MAPK, PKA, PKC, PI3K and CaMKII may be involved in downstream signaling for activation of NMDA receptors. Interestingly, dihydrotestosterone suppressed the E2-LTP. We also investigated rapid changes of dendritic spines (=postsynapses) in response to E2, using hippocampal slices from adult male rats. We found 1 nM E2 increased the density of spines by approximately 1.3-fold within 2 h by imaging Lucifer Yellow-injected CA1 pyramidal neurons. The E2-induced spine increase was blocked by ICI. The increase in spines was suppressed by blocking PI3K, Erk MAPK, p38 MAPK, PKA, PKC, LIMK, CaMKII or calcineurin, individually. On the other hand, blocking JNK did not inhibit the E2-induced spine increase. Taken together, these results suggest that E2 rapidly induced LTP and also increased the spine density through kinase networks that are driven by synaptic ER. This article is part of a Special Issue entitled SI: Brain and Memory.

This article is part of a Special Issue “Estradiol and cognition”. Estradiol (E2) is locally synthesized within the hippocampus and the gonads. Rapid modulation of hippocampal synaptic plasticity by E2 is essential for synaptic regulation. The molecular mechanisms of modulation through the synaptic estrogen receptor (ER) and its downstream signaling, however, are largely unknown in the dentate gyrus (DG). We investigated the E2-induced modulation of dendritic spines in male adult rat hippocampal slices by imaging Lucifer Yellow-injected DG granule cells. Treatments with 1 nM E2 increased the density of spines by approximately 1.4-fold within 2 h. Spine head diameter analysis showed that the density of middle-head spines (0.4–0.5 μm) was significantly increased. The E2-induced spine density increase was suppressed by blocking Erk MAPK, PKA, PKC and LIMK. These suppressive effects by kinase inhibitors are not non-specific ones because the GSK-3β antagonist did not inhibit E2-induced spine increase. The ER antagonist ICI 182,780 also blocked the E2-induced spine increase. Taken together, these results suggest that E2 rapidly increases the density of spines through kinase networks that are driven by synaptic ER.

We investigated the immunohistochemical localization of tenascin-C in 8-week-old rat periodontal ligaments. Tenascin-C immunoreactivity was detected in zones along with cementum and alveolar bone, and more intensely on the resorption surface of alveolar bone than on the formation surface. On the resorbing surface, tenascin-C immunoreactivity was detected in Howship's lacunae without osteoclasts, and in the interfibrous space of the periodontal ligaments, indicating that this molecule works as an adhesion molecule between bone and fibers of periodontal ligaments. Upon experimental tooth movement by inserting elastic bands (Waldo method), the physiological resorption surface of alveolar bone under compressive force showed enhanced bone resorption and enhanced tenascin-C immunoreactivity. However, on the physiological bone formation surface under compressive force, bone resorption was seen only occasionally, and no enhanced tenascin-C immunoreactivity was noted. In an experiment involving excessive occlusal loading to rat molars, transient bone resorption occurred within interradicular septa, but no enhanced tenascin-C immunoreactivity was seen in the periodontal ligaments. These results indicate that tenascin-C works effectively on the bone resorbing surface of physiological alveolar bone remodeling sites, rather than on the non-physiological transient bone resorbing surface. Fibronectin immunoreactivity was distributed evenly in the periodontal ligaments under experimental conditions. Co-localization of tenascin-C and fibronectin immunoreactivity was observed in many regions, but mutually exclusive expression patterns were also seen in some regions, indicating that fibronectin might not be directly involved in alveolar bone remodeling, but may play a role via interaction with tenascin-C.

The purpose of the present study was to histopathologically and immunohistochemically investigate the distribution of proteoglycans in human periodontal ligament (PDL). Specimens from osteotomy and tooth extraction having healthy PDL were studied. Histologically, PDL consisted of fibrous tissues, involving a compact arrangement area and edematous or myxoid area. Immuno-histochemically, versican binding region (12C5), versican link protein (8A4) and biotinylated hyaluronic acid binding protein (B-HABP) were distributed in PDL. In addition, positive immunore-activity for 12C5 and 8A4 was stronger in the compact arrangement area than in the edematous or myxoid area. Reactivity for B-HABP was stronger in the edematous or myxoid area than in the compact fibrous area. These results suggest that versican and link protein are associated with fibrous tissues, whereas hyaluronic acid is related to the formation of edematous and/or myxoid tissue in human PDL. These substances may play a role in periodontal homeostasis by protecting against mechanical stress.

Objective To investigate if mandibular condylar cartilage is derived from the periosteum of the ossifying mandible or from a separate, programmed blastema. Materials and methods Fetal mice at E14.0–16.0, fetal rats at E16.0–18.0, and human embryos at 9 and 10wks of gestation were used. The initial formation of rat condylar cartilage was investigated by using serial sections and enzyme-histochemistry to detect alkaline phosphatase activity. Histological observations of serial sections of human fetuses as well as 3D-reconstruction models were also analyzed. The expression of collagen type mRNA in developing rat condylar cartilage was directly compared with that in mice by performing in situ hybridization. Results An anlage of the rat condylar process (condylar anlage) was clearly identified in the posterior position of the ossifying mandible and was continuous with it at E16.0. Newly formed rat condylar cartilage was observed at E16.5 and was continuous with the ossifying mandible. Mesenchymal cells in the condylar anlage at E16.0 showed alkaline phosphatase activity and chondrocytes in the newly formed condylar cartilage also showed enzymatic activity. Thus, rat mandibular condylar cartilage that derives from alkaline phosphatase-positive periosteum-like cells is continuous with the ossifying mandible, as previously demonstrated in mice, but rapid differentiation into hypertrophic chondrocytes in rats is not remarkable compared to that in mice. The condylar anlage and the newly formed cartilage were also continuous with the ossifying mandible in human embryos. Conclusions Mammalian mandibular condylar cartilage derives from the periosteum of the ossifying mandible in mice, rats, and humans.

Multiprotein bridging factor 1 (MBF1) is a highly conserved transcriptional co-activator involved in the regulation of diverse processes, such as environmental stress responses. We recently identified a novel MBF1 gene, PyMBF1, from the marine red alga Pyropia yezoensis. In this study, quantitative real-time PCR analysis revealed that PyMBF1 transcripts were upregulated in P. yezoensis cells during exposure to oxidative and heat stresses. We also examined heat signaling in P. yezoensis cells by monitoring the accumulation of PyMBF1 transcripts. Heat activation of PyMBF1 was inhibited by the membrane rigidifier dimethylsulfoxide, whereas it was induced without heat stress by the membrane fluidizer benzyl alcohol (BA). Induction of PyMBF1 transcripts by heat and BA was inhibited by 1-butanol, an inhibitor of phospholipase D (PLD). The results suggest that the heat activation of PyMBF1 requires membrane fluidization and activation of PLD. These findings provide an initial step toward understanding heat signaling in marine red algae.

Accurate 3D determination of postsynaptic structures is essential to our understanding memory-related function and pathology in neurons. However, current methods of spine analysis require time-consuming and labor-intensive manual spine identification in large image data sets. Therefore, a realistic implementation of algorithm is necessary to replace manual identification. Here, we describe a new method for the automated detection of spines and dendrites based on analysis of geometrical features. Our “Spiso-3D” software carries out automated dendrite reconstruction and spine detection using both eigenvalue images and information of brightness, avoiding detection of pseudo-spines. To demonstrate the potential application of Spiso-3D automated analysis, we distinguished the rapid effects of androgen and estrogen on rapid modulation of spine head diameter in the hippocampus. These findings advance our understanding of neurotrophic function of brain sex steroids. Our method is expected to be valuable to analyze vast amounts of dendritic spines in neurons in the mammalian cerebral cortex.

The reaction section of the naphtha hydro-desulfurization (HDS) process is a heating and cooling thermal process consisting of a feed/effluent heat exchanger and a fired heater. Energy savings are fundamentally made as a result of the maximized heat recovery in the heat exchanger and the reduced heat duty of the fired heater. To achieve further energy saving in the process, “self-heat recuperation technology” (SHRT) was adopted. In this technology, a compressor was introduced. The suction side of the compressor needed a lower pressure and the feed stream evaporated much easily. The discharged side of the compressor satisfied the operating conditions of both pressure and temperature at the inlet of the reactor. And the reactor effluent stream was able to be used completely to preheat and vaporize the feed stream. All the heat in the process stream was re-circulated without using a fired heater. SHRT was applied to the naphtha HDS process of 18,000 barrel per stream day (BPSD) in the refinery and the mass and energy balance of the process was calculated using commercially available simulation software, Invensys PROII version 8.1. This process-simulation case study confirmed that despite there being no more energy saving potential in the conventional process that makes use of a fired heater, the advanced process with SHRT can reduce the energy consumption significantly by using the recuperated heat of the feed stream.

Modulation of hippocampal synaptic plasticity by androgen has been attracting much attention. Thorns of thorny excrescences of CA3 hippocampal neurons are post-synaptic regions whose presynaptic partners are mossy fiber terminals. Here we demonstrated rapid effects of dihydrotestosterone (DHT) and testosterone (T) on the density of thorns, by imaging Lucifer Yellow-injected neurons in adult male rat hippocampal slices. The application of 10 nM DHT or T induced rapid increase in the density of thorns within 2 h. The androgen-mediated increase was suppressed by blocking several kinases, such as Erk MAPK, p38 MAPK, PKC, and CaMKII. On the other hand, PKA, PI3K were not involved in the signaling of thorn-genesis. The increase in the thorn density by androgen was also blocked by the inhibitor of classical androgen receptor. Almost no difference was observed between DHT and T in the effect on the thorn density. We observed that the androgen-induced thorn-genesis is opposite to estrogen-induced thorn-degeneration.

分子動力学シミュレーションを行うとき、時間刻みをどの程度まで大きく取ることができるのか、その許容範囲について調べた。積分方法はベルレ法を用い、時間刻み幅を0.02フェムト秒(fs)から3.0 fs まで増大させた。5種類のアミノ酸（Glycine, Alanine, Valine, Leucine, Isoleucine ）3量体を計算対象とした。基準時間刻み(0.02 fs)とその他の時間刻みについてのエネルギー差の平均値は、時間刻み幅のほぼ2乗で増加するが、標準偏差は時間刻み0.5 fsから1.5 fsまではほとんど差がみられなかった。つまり、この範囲内ではどの時間刻みでシミュレーションを行ってもあまり差がない。ゆえに、今回の例の場合、時間刻み1.5 fs付近でシミュレーションを行うのが時間短縮の面から効果的である事が示唆された。

We developed a new desiccator system by improving the conventional desiccator method and measured the FA-removal effects of adsorbents using this system. The improved desiccator system consists of: 1) a pump, 2) a flow meter, 3) a FA gas generator, 4) five connected desiccators, and 5) an exhaust. A more stable concentration of FA in the desiccators was obtained when they were connected in series rather than in parallel. The FA removal rate for 3 days for red tea in used tea bags, green tea, oolong tea, or powdered coffee was more than 80%, and the removal rates for 1 day by activated carbon from palm nutshells and silica gel, as commercially available chemical agents, were 100% and 75%, respectively. This improved desiccator system allows direct collection of air in the desiccator, and may have wide applications.

A field experiment on the heat accumulation of solar ponds was carried out using low concentration salt water. The solar pond system exhibited certain heat accumulation, by being taken the special measures, in a relatively short period (1-3 weeks). The temperature in the lower layer was about 6°C higher than that in the upper layer, in addition, maximally about 15°C higher than the air temperature in the night-time. The accumulated heat in the lower layer of the solar pond could be used for heating relatively narrow spaces, for example, rooms in general houses and greenhouses in farms.

Flexible electronics such as foldable smartphones and electronic paper are expected to develop the market. Conductive wires for sending electric signals are necessary for electronic devices, and the requirements for them are electronic conductivity, mechanical flexibility and adhesiveness to a substrate. In addition, an efficient process is required for fabrication of the interconnect. Although metals such as copper and silver have been used for the interconnect of the conventional electronic devices which are mostly rigid, the metal interconnect might be broken and peeled off from the plastic substrate when they are bent and unbent repeatedly. As compared to metal, organic polymers have excellent mechanical properties while their conductivity are comparatively low. Therefore, composites of polymer and metal have been studied in order to achieve both electrical conductivity and mechanical flexibility. So far, the following research results were reported; that conducive polymer/metal composite showed 2×10-4 Ω-1·cm-1 of conductivity two orders of magnitude higher than the commercially available conductive polymer, more than 90% of adhesiveness onto various plastic materials, and 104times of repeated bending with keeping electrical conduction. The electrical and mechanical behavior of the composite, however, are not clear when the composite is in motion. The purpose of this research was to clarify dynamic electrical and mechanical characteristic of the conductive polymer/metal composite film. A mixture of AgBF4 and C4H5N in acetonitrile was used as the reaction solution. It was dropped in the linear shape on a polyimide (PI) sheet and polydimethylsiloxane (PDMS) sheet as the substrate. UV light was irradiated on the reaction solution for 5 minutes and composite of polypyrrole doped with BF4and metal silver was synthesized. Mechanical property of the composite on polyimide was evaluated by a tensile test according to the Japanese Industrial Standards (JIS 7127) with a load cell of 9.8 N and at a tensile speed of 10 mm·min-1. During the tensile test, the electric resistance between two ends of the specimens was measured. The tested specimens were observed by microscopies. From changes in applied force with tensile time of the polypyrrole/silver composite formed on the PI substrate, a breaking of the specimen, i.e. corresponding to the substrate was observed at 63 sec under the test load of 321 N while the specimen with PDMS substrate was broken at 168 sec under 181 N. From changes in electric resistance with tensile time of polypyrrole/silver composite formed on the PI substrate, the electric resistance was increased with the time, i.e. the strain, and it exceeded the upper limit of measurement at 63 sec after starting of the tensile test. The former behaviour was explained by decreasing in contact area between the silver particles of the composite and the latter was due to breaking of both the composite and the substrate at the same time. In the case of the specimen with the PDMS substrate, the electric resistance was almost constant from the tensile start to 55 sec and then increased gradually until 83 sec, jumped up to the upper limit of measurement at 89 sec through up and down behaviour. Considerable difference of change in electric resistance between the substrates until breaking of the composite might be caused by actual tensile stress applied to the composite formed on the substrate with different shearing stress depending on adhesive status between the composite and the substrate. In addition, it is noted that the composite can be used until the polyimide substrate is broken in flexible electronic devices while the mechanical behaviour of the composite until the composite is broken can be evaluated by using PDMS as the substrate. The load stress and the strain at the breaking of the composite were calculated 158 N·mm-2 and 17.4% for the PI substrate and 113 N·mm-2and 24.7% for the PDMS substrate, respectively. From these values, it was estimated that the composite was stretched 1.74 mm and 2.71 mm for the PI and PDMS substrates, respectively at the breaking point. From the elongation of metallic silver as one of the wiring materials is 23%, it is supposed that the composite material used in this study can exhibit improvement up to 27.1% higher than that of metallic silver alone in terms of conductive elongation. This research succeeded in evaluating both mechanical and electrical properties of conductive polymer/metal composite simultaneously for the first time. Dynamic mechanical and electrical characteristic of the conductive polymer/metal composite was clarified; the composite is superior to metallic silver as the interconnect of the flexible devices and can be used until the polyimide substrate is broken. Figure 1

The light-harvesting chlorophyll a/b binding protein complex of photosystem II (LHCII) is the main antenna complex of photosystem II (PSII). Plants change their LHCII content depending on the light environment. Under high-light conditions, the content of LHCII should decrease because over-excitation damages the photosystem. Chlorophyll b is indispensable for accumulating LHCII, and chlorophyll b degradation induces LHCII degradation. Chlorophyll b degradation is initiated by chlorophyll b reductase (CBR). In land plants, NON-YELLOW COLORING 1 (NYC1) and NYC1-Like (NOL) are isozymes of CBR. We analyzed these mutants to determine their functions under high-light conditions. During high-light treatment, the chlorophyll a/b ratio was stable in the wild-type (WT) and nol plants, and the LHCII content decreased in WT plants. The chlorophyll a/b ratio decreased in the nyc1 and nyc1/nol plants, and a substantial degree of LHCII was retained in nyc1/nol plants after the high-light treatment. These results demonstrate that NYC1 degrades the chlorophyll b on LHCII under high-light conditions, thus decreasing the LHCII content. After the high-light treatment, the maximum quantum efficiency of the PSII photochemistry was lower in nyc1 and nyc1/nol plants than in WT and nol plants. A larger light-harvesting system would damage PSII in nyc1 and nyc1/nol plants. The fluorescence spectroscopy of the leaves indicated that photosystem I was also damaged by the excess LHCII in nyc1/nol plants. These observations suggest that chlorophyll b degradation by NYC1 is the initial reaction for the optimization of the light-harvesting capacity under high-light conditions.

The home drip infusion is a stressful procedure for both patients and families under HPN at home. Effective and reliable guidance for drip infusion management should be provided while patients are still at the hospital to realize reliable home care. We revised the HPN Guidance Manual and report the process in this article. We revised the manual according to the principles that "the guidance is subdivided into 3 steps so that the contents of the guidance can be adjusted for individual patients", that "a lot of photos and illustrations for frequently used 2 models are placed" and that "a video is prepared to make the most of the impact motion pictures can give". We want to use the manual in future clinical practices.