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LILRB4 (B4, also known as ILT3/CD85k) is an immune checkpoint of myeloid lineage cells, albeit its mode of function remains obscure. Our recent identification of a common ligand for both human B4 and its murine ortholog gp49B as the fibronectin (FN) N-terminal 30 kDa domain poses the question of how B4/gp49B regulate cellular activity upon recognition of FN in the plasma and/or the extracellular matrix. Since FN in the extracellular matrix is tethered by FN-binding integrins, we hypothesized that B4/gp49B would tether FN in cooperation with integrins on the cell surface, thus they should be in close vicinity to integrins spatially. This scenario suggests a mode of function of B4/gp49B by which the FN-induced signal is regulated. The FN pull-down complex was found to contain gp49B and integrin β 1 in bone marrow-derived macrophages. The confocal fluorescent signals of the three molecules on the intrinsically FN-tethering macrophages were correlated to each other. When FN-poor macrophages adhered to culture plates, the gp49–integrin β 1 signal correlation increased at the focal adhesion, supporting the notion that gp49B and integrin β 1 become spatially closer to each other there. Adherence of RAW264.7 and THP-1 cells to immobilized FN induced phosphorylation of spleen tyrosine kinase, whose level was augmented under B4/gp49B deficiency. Thus, we concluded that B4/gp49B can co-tether FN in cooperation with integrin in the cis configuration on the same cell, forming a B4/gp49B–FN–integrin triplet as a regulatory unit of a focal adhesion-dependent pro-inflammatory signal in macrophages.

Vascular endothelial cells (ECs) respond to mechanical stimuli caused by blood flow to maintain vascular homeostasis. Although the oxygen level in vascular microenvironment is lower than the atmospheric one, the cellular dynamics of ECs under hypoxic and flow exposure are not fully understood. Here, we describe a microfluidic platform for the reproduction hypoxic vascular microenvironments. Simultaneous application of hypoxic stress and fluid shear stress to the cultured cells was achieved by integrating a microfluidic device and a flow channel that adjusted the initial oxygen concentration in a cell culture medium. An EC monolayer was then formed on the media channel in the device, and the ECs were observed after exposure to hypoxic and flow conditions. The migration velocity of the ECs immediately increased after flow exposure, especially in the direction opposite to the flow direction, and gradually decreased, resulting in the lowest value under the hypoxic and flow exposure condition. The ECs after 6-h simultaneous exposure to hypoxic stress and fluid shear stress were generally aligned and elongated in the flow direction, with enhanced VE-cadherin expression and actin filament assembly. Thus, the developed microfluidic platform is useful for investigating the dynamics of ECs in vascular microenvironments.

A myeloid immune checkpoint, leukocyte immunoglobulin-like receptor (LILR) B4 (B4, also known as ILT3/CD85k in humans and gp49B in mice) is expressed on dendritic cells (DCs). However, a mode of regulation of DCs by B4/gp49B is not identified yet in relation to the ligand(s) as well as to the counteracting, activation-type receptor. Our recent identification of the physiological/pathological ligand for B4/gp49B as the fibronectin (FN) N-terminal 30-kDa domain poses the question of the relationship between B4/gp49B and a classical FN receptor/cellular activator, integrin, on DCs. Here we showed that FN is not constitutively tethered on the surface of bone marrow-derived cultured DCs (BMDCs) or splenic DCs, even though the FN receptor integrin and gp49B are co-expressed on these cells. Confocal laser scanning microscopic analysis, however, revealed weak correlation of fluorescent signals between gp49B and integrin β

We have developed a continuous microwave irradiation-assisted Buchwald–Hartwig amination using our original Pd nanoparticle catalyst with a copper plate as a co-existing metal solid. In this methodology, a microwave-controlled product selectivity was achieved between Buchwald–Hartwig amination and aryne amination performed under strongly basic conditions and at a high reaction temperature, because a polar chemical species such as Ar–Pd–halogen might be activated selectively by microwave radiation. Moreover, our catalyst could be used repeatedly over 10 times, and the amount of Pd leaching could be suppressed to a low level.

Monoamine oxidase B (MAO-B) metabolizes monoamines such as dopamine regarding neural transmission and controls its level in the mammalian's brain. When MAO-B metabolizes dopamine abnormally, normal neurotransmission does not occur, and central nervous system disorders such as Parkinson's disease may develop. Although several MAO inhibitors have been developed, most of them have no selectivity between monoamine oxidase A (MAO-A) and MAO-B, or they work irreversibly against the enzyme. This report describes the first case of screening of

Intermittent parathyroid hormone (iPTH) treatment induces bone anabolic effects that result in the recovery of osteoporotic bone loss. Human PTH is usually given to osteoporotic patients because it induces osteoblastogenesis. However, the mechanism by which PTH stimulates the expansion of stromal cell populations and their maturation toward the osteoblastic cell lineage has not be elucidated. Mouse genetic lineage tracing revealed that iPTH treatment induced osteoblastic differentiation of bone marrow (BM) mesenchymal stem and progenitor cells (MSPCs), which carried the leptin receptor (LepR)-Cre. Although these findings suggested that part of the PTH-induced bone anabolic action is exerted because of osteoblastic commitment of MSPCs, little is known about the in vivo mechanistic details of these processes. Here, we showed that LepR+ MSPCs differentiated into type I collagen (Col1)+ mature osteoblasts in response to iPTH treatment. Along with osteoblastogenesis, the number of Col1+ mature osteoblasts increased around the bone surface, although most of them were characterized as quiescent cells. However, the number of LepR-Cre-marked lineage cells in a proliferative state also increased in the vicinity of bone tissue after iPTH treatment. The expression levels of SP7/osterix (Osx) and Col1, which are markers for osteoblasts, were also increased in the LepR+ MSPCs population in response to iPTH treatment. In contrast, the expression levels of Cebpb, Pparg, and Zfp467, which are adipocyte markers, decreased in this population. Consistent with these results, iPTH treatment inhibited 5-fluorouracil- or ovariectomy (OVX)-induced LepR+ MSPC-derived adipogenesis in BM and increased LepR+ MSPC-derived osteoblasts, even under the adipocyte-induced conditions. Treatment of OVX rats with iPTH significantly affected the osteoporotic bone tissue and expansion of the BM adipose tissue. These results indicated that iPTH treatment induced transient proliferation of the LepR+ MSPCs and skewed their lineage differentiation from adipocytes toward osteoblasts, resulting in an expanded, quiescent, and mature osteoblast population. © 2019 American Society for Bone and Mineral Research.

We have explored the effect of a co-existing metal in the ligand-free Suzuki–Miyaura coupling reaction of an aryl chloride, which is promoted by a “continuous irradiation type microwave” and a “palladium nanoparticle catalyst”, and found that the co-existing metal affects this reaction due to its absorption ability of microwave energy in the reaction system. We also observed that spiking occurred more frequently in the presence of a co-existing metal.

The use of grid-connected distributed generators (DGs) is increasing rapidly in Japan. In the distribution system with large-scale DG installations, the reverse power flow from DGs leads to a decrease in the line voltage due to the changes in the voltage phase; this is not well-known as the voltage drop phenomenon. As a result, it is difficult to estimate distribution voltages with the conventional voltage-estimation method based on only the measured information when the power flow in the distribution system is different from the measured voltage. To address the estimation problem, in this paper, we propose a simple voltage-estimation method that integrates the facility information about the medium-voltage power distribution system with the measured information. Numerical simulations have been performed to validate this method using the distribution system model and the conventional voltage estimation model. The proposed method achieves a voltage estimation with higher accuracy as compared to that estimated by the conventional method.

We previously reported that daily administration of a pharmacological dose of eldecalcitol, an analog of 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], increased bone mass by suppressing bone resorption. These antiresorptive effects were found to be mediated by the vitamin D receptor (VDR) in osteoblast-lineage cells. Using osteoblast-lineage-specific VDR conditional knockout (Ob-VDR-cKO) mice, we examined whether proresorptive activity induced by the high-dose 1α,25(OH)2D3 was also mediated by VDR in osteoblast-lineage cells. Administration of 1α,25(OH)2D3 (5 μg/kg body weight/day) to wild-type mice for 4 days increased the number of osteoclasts in bone and serum concentrations of C-terminal crosslinked telopeptide of type I collagen (CTX-I, a bone resorption marker). The stimulation of bone resorption was concomitant with the increase in serum calcium (Ca) and fibroblast growth factor 23 (FGF23) levels, and decrease in body weight. This suggests that a toxic dose of 1α,25(OH)2D3 can induce bone resorption and hypercalcemia. In contrast, pretreatment of wild-type mice with neutralizing anti-receptor activator of NF-κB ligand (RANKL) antibody inhibited the 1α,25(OH)2D3-induced increase of osteoclast numbers in bone, and increase of CTX-I, Ca, and FGF23 levels in serum. The pretreatment with anti-RANKL antibody also inhibited the 1α,25(OH)2D3-induced decrease in body weight. Consistent with observations in mice conditioned with anti-RANKL antibody, the high-dose administration of 1α,25(OH)2D3 to Ob-VDR-cKO mice failed to significantly increase bone osteoclast numbers, serum CTX-I, Ca, or FGF23 levels, and failed to reduce the body weight. Taken together, this study demonstrated that the proresorptive, hypercalcemic, and toxic actions of high-dose 1α,25(OH)2D3 are mediated by VDR in osteoblast-lineage cells.

Bone tissues have trabecular bone with a high bone turnover and cortical bone with a low turnover. The mechanisms by which the turnover rate of these bone tissues is determined remain unclear. Osteocytes secrete sclerostin, a Wnt/β-catenin signaling antagonist, and inhibit bone formation. We found that sclerostin expression in cortical bone is more marked than in trabecular bone in Sost reporter mice. Leukemia inhibitory factor (LIF) secreted from osteoclasts reportedly suppressed sclerostin expression and promoted bone formation. Here, we report that osteoclasts downregulate sclerostin expression in trabecular bone and promote bone turnover. Treatment of C57BL/6 mice with an anti-RANKL antibody eliminated the number of osteoclasts and LIF-positive cells in trabecular bone. The number of sclerostin-positive cells was increased in trabecular bone, while the number of β-catenin-positive cells and bone formation were decreased in trabecular bone. Besides, Tnfsf11 heterozygous (Rankl+/−) mice exhibited a decreased number of LIF-positive cells and increased number of sclerostin-positive cells in trabecular bone. Rankl+/− mice exhibited a decreased number of β-catenin-positive cells and reduced bone formation in trabecular bone. Furthermore, in cultured osteoclasts, RANKL stimulation increased Lif mRNA expression, suggesting that RANKL signal increased LIF expression. In conclusion, osteoclasts downregulate sclerostin expression and promote trabecular bone turnover.

Active forms of vitamin D enhance osteoclastogenesis in vitro and in vivo through the vitamin D receptor (VDR) in osteoblast-lineage cells consisting of osteoblasts and osteocytes. This pro-resorptive activity was evident basically with higher concentrations of active vitamin D than those expected in physiological conditions. Nevertheless, vitamin D compounds have been used in Japan for treating osteoporosis to increase bone mineral density (BMD). Of note, the increase in BMD by long-term treatment with pharmacological (=near-physiological) doses of vitamin D compounds was caused by the suppression of bone resorption. Therefore, whether vitamin D expresses pro-resorptive or anti-resorptive properties seems to be dependent on the treatment protocols. We established osteoblast lineage-specific and osteoclast-specific VDR conditional knockout (cKO) mice using Osterix-Cre transgenic mice and Cathepsin K-Cre knock-in mice, respectively. According to our observation using these cKO mouse lines, neither VDR in osteoblast-lineage cells nor that in osteoclasts played important roles for osteoclastogenesis and bone resorption at homeostasis. However, using our cKO lines, we observed that VDR in osteoblast-lineage cells, but not osteoclasts, was involved in the anti-resorptive properties of pharmacological doses of vitamin D compounds in vivo. Two different osteoblast-lineage VDR cKO mouse lines were reported. One is a VDR cKO mouse line using alpha 1, type I collagen (Col1a1)-Cre transgenic mice (here we call Col1a1-VDR-cKO mice) and the other is that using dentin matrix protein 1 (Dmp1)-Cre transgenic mice (Dmp1-VDR-cKO mice). Col1a1-VDR-cKO mice exhibited slightly increased bone mass due to lowered bone resorption. In contrast, Dmp1-VDR-cKO mice exhibited no difference in BMD in agreement with our results regarding Ob-VDR-cKO mice. Here we discuss contradictory results and multiple modes of actions of vitamin D in bone resorption in detail. (279 words).

Bone formation is coupled to bone resorption throughout life. However, the coupling mechanisms are not fully elucidated. Using Tnfrsf11b-deficient (OPG-/- ) mice, in which bone formation is clearly coupled to bone resorption, we found here that osteoclasts suppress the expression of sclerostin, a Wnt antagonist, thereby promoting bone formation. Wnt/β-catenin signals were higher in OPG-/- and RANKL-transgenic mice with a low level of sclerostin. Conditioned medium from osteoclast cultures (Ocl-CM) suppressed sclerostin expression in UMR106 cells and osteocyte cultures. In vitro experiments revealed that osteoclasts secreted leukemia inhibitory factor (LIF) and inhibited sclerostin expression. Anti-RANKL antibodies, antiresorptive agents, suppressed LIF expression and increased sclerostin expression, thereby reducing bone formation in OPG-/- mice. Taken together, osteoclast-derived LIF regulates bone turnover through sclerostin expression. Thus, LIF represents a target for improving the prolonged suppression of bone turnover by antiresorptive agents. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

Long-term treatment with active vitamin D [1α,25(OH)2D3] and its derivatives is effective for increasing bone mass in patients with primary and secondary osteoporosis. Derivatives of 1α,25(OH)2D3, including eldecalcitol (ELD), exert their actions through the vitamin D receptor (VDR). ELD is more resistant to metabolic degradation than 1α,25(OH)2D3. It is reported that ELD treatment causes a net increase in bone mass by suppressing bone resorption rather than by increasing bone formation in animals and humans. VDR in bone and extraskeletal tissues regulates bone mass and secretion of osteotropic hormones. Therefore, it is unclear what types of cells expressing VDR preferentially regulate the vitamin D–induced increase in bone mass. Here, we examined the effects of 4-week treatment with ELD (50 ng/kg/day) on bone using osteoblast lineage-specific VDR conditional knockout (Ob-VDR-cKO) and osteoclast-specific VDR cKO (Ocl-VDR-cKO) male mice aged 10 weeks. Immunohistochemically, VDR in bone was detected preferentially in osteoblasts and osteocytes. Ob-VDR-cKO mice showed normal bone phenotypes, despite no appreciable immunostaining of VDR in bone. Ob-VDR-cKO mice failed to increase bone mass in response to ELD treatment. Ocl-VDR-cKO mice also exhibited normal bone phenotypes, but normally responded to ELD. ELD-induced FGF23 production in bone was regulated by VDR in osteoblast-lineage cells. These findings suggest that the vitamin D treatment-induced increase in bone mass is mediated by suppressing bone resorption through VDR in osteoblast-lineage cells. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

Resonant acoustic® mixing (RAM) technology is a system that performs high-speed mixing by vibration through the control of acceleration and frequency. In recent years, real-time process monitoring and prediction has become of increasing interest, and process analytical technology (PAT) systems will be increasingly introduced into actual manufacturing processes. This study examined the application of PAT with the combination of RAM, near-infrared spectroscopy, and chemometric technology as a set of PAT tools for introduction into actual pharmaceutical powder blending processes. Content uniformity was based on a robust partial least squares regression (PLSR) model constructed to manage the RAM configuration parameters and the changing concentration of the components. As a result, real-time monitoring may be possible and could be successfully demonstrated for in-line real-time prediction of active pharmaceutical ingredients and other additives using chemometric technology. This system is expected to be applicable to the RAM method for the risk management of quality.

We developed a conceptually and methodologically novel ruthenium(0) nanoparticle catalyst, sulfur-modified Au-supported ruthenium nanoparticles (SARu). SARu is easily prepared through a three-step procedure involving simultaneous in situ metal nanoparticle and nanospace organization. This unique method does not require any conventional preformed template to immobilize and stabilize metal nanoparticles. SARu is an ideal ruthenium catalyst for liquid-phase combinatorial synthesis because it repeatedly catalyzes ligand-free Suzuki–Miyaura coupling of aryl halides, including aryl chlorides, with arylboronic acids with low Ru leaching. Physical analysis of SARu showed that the active species in these reactions were ruthenium (0) nanoparticles with a size of 1–3 nm. Also, we developed a continuously irradiating microwave methodology, which can first time discriminate the heating effect and the microwave effect in microwave experiments.

PVs have been rapidly incorporated within power distribution systems after the operation of Feed In Tariff (FIT). Step Voltage Regulator (SVR) with Line Drop Compensator method has been installed to the power distribution system to control rising voltages due to the reverse flow from PVs. LDC controls the distribution voltage based on the estimated voltage obtained via sensor measurements in real-time. However, using LDC, it is difficult to maintain the distribution voltage within a specified range because the estimation error expands with increasing PV installed capacity. In Japan, a type of automatic switch with voltage and current sensors (IT-switch) has been installed to detect an accident point in the power distribution system. IT-switching can monitor line voltage and current in each phase, and measured data are transferred to data servers. This paper proposes an advanced, autonomous voltage-control method to improve the estimation accuracy and voltage control performance of SVR, using the reference database to address the voltage deviation problem. The proposed method estimates a voltage width of the control target voltage in real-time as a reference voltage by using the measured (online) data and database (offline) data. To determine the validity of the proposed method, we conducted numerical simulations and compared the voltage control performance and the influence of SVR life span using a model power distribution system. The results indicates that the proposed method improved the voltage control performance and SVR life span by improving the estimation accuracy through the integration of real-time measured data and the reference database.

Mixing processes are important for making high-quality pharmaceutical formulations and are related to dissolution and chemical stability in pharmaceutical manufacturing. The resonant acoustic® mixing (RAM) technology is a blending method, and it has been reported that it has a unique mixing action for various samples. In this study, in order to apply the RAM method to the pharmaceutical blending process, optimization of the operating conditions of RAM (acceleration and frequency) was conducted by numerical simulation. Powder mixing experiments were carried out using various RAM conditions and also a modified V-shaped mixing device with a powder material of theophylline powder and lactose or magnesium oxide and lactose. The angle of repose of the mixed powder sample was measured as an index of powder flowability and also the degree of powder mixing. A drug uniformity test of the mixed powders was performed to measure theophylline content using high-performance liquid chromatography. The results of these experiments indicate that the optimum values for acceleration and frequency in RAM mixing are 90–100 G and approximately 60 Hz, respectively, which prove the superiority of the RAM method over the ordinary mixing method. The RAM method was estimated to throw the powder upward into the air and perform mixing by utilizing free-fall, possibly by inducing a weightless state without depending on the density and mass of the sample. Therefore, RAM may be applicable to pharmaceutical manufacturing processes.

To effectively utilize a photovoltaic (PV) system, reactive-power control methods for solar inverters have been considered. Among the various methods, the constant-voltage control outputs less reactive power compared with the other methods. We have developed a constant-voltage control to reduce the reactive-power output. However, the developed constant-voltage control still outputs unnecessary reactive power because the control parameter is constant in every waveform of the PV output. To reduce the reactive-power output, we propose a dynamic reactive-power control method with a PV output prediction. In the proposed method, the control parameter is varied according to the properties of the predicted PV waveform. In this study, we performed numerical simulations using a distribution system model, and we confirmed that the proposed method reduces the reactive-power output within the voltage constraint.

Vitamin D compounds, 1,25(OH)2D3 and its analogs, enhance osteoclastogenesis in vitro and in vivo through the vitamin D receptor (VDR) in osteoblastic cells. This proresorptive activity was detected only with much higher concentrations of vitamin D compounds than those expected in physiological conditions. On the other hand, these compounds have been used as therapeutic drugs in Japan for treating osteoporosis to increase bone mineral density (BMD). Notably, the increase in BMD by long-term treatment with pharmacological doses of vitamin D compounds is caused by the suppression of bone resorption. Therefore, whether vitamin D expresses proresorptive or antiresorptive properties seemingly depends on the treatment protocols. We established osteoblastic cell-specific and osteoclast-specific VDR conditional knockout mice. Neither VDR in osteoblastic cells nor that in osteoclasts plays important roles for osteoclastogenesis at homeostasis. However, VDR in osteoblastic cells, but not osteoclasts, was involved in the antiresorptive properties of pharmacological doses of vitamin D compounds in vivo. Multiple modes of action of vitamin D in bone resorption are discussed in detail in this chapter.

Compensation of a voltage within the appropriate range becomes difficult when a large number of photovoltaic (PV) systems are installed. As a solution to this problem, the installation of a low-voltage regulator (LVR) has been studied. In this paper, we propose a method for instantly and accurately determining the line drop compensator (LDC) method parameters as a part of a voltage management scheme, which consists of prediction, operation, and control. In the proposed method, the solution candidates of the proper LDC parameters are narrowed by using a random forest that learns the relationship between the power-series data and the properness of the LDC parameters, thereby reducing the computational cost. We performed numerical simulations to verify the validity of the proposed method. From the results, the LDC parameters can be rapidly and accurately determined. Additionally, the desirable voltage control performance is verified.

The canonical Wnt/β-catenin signaling pathway in osteoblast-lineage cells inhibits osteoclastogenesis through the expression of osteoprotegerin (Opg), a decoy receptor of receptor activator of Nf-κb (Rank) ligands. Wnt5a, a typical non-canonical Wnt ligand, enhances the expression of Rank in osteoclast precursors, which, in turn, promotes the Rank ligand (Rankl)-induced formation of osteoclasts. In contrast, Wnt16 and Wnt4 have been shown to inhibit the Rankl-induced formation of osteoclasts through non-canonical Wnt signals. However, the relationships among these Wnt ligands in osteoclastogenesis remained to be elucidated. We herein showed that Wnt16, but not Wnt4, inhibited the Rankl-induced osteoclastogenesis in bone marrow-derived macrophage (BMM) cultures. Wnt3a and Wnt4 inhibited the 1α,25-dihydroxy vitamin D3 (1,25D3)-induced osteoclastogenesis in co-cultures prepared from wild-type mice, but not in those from Opg–/– nice. Wnt16 inhibited the 1,25D3-induced formation of osteoclasts in both wild-type and Opg–/– co-cultures. Wnt16, Wnt4, and Wnt3a failed to inhibit the pit-forming activity of osteoclasts. Wnt16 failed to inhibit the Wnt5a-induced expression of Rank in osteoclast precursors. In contrast, Wnt5a abrogated the inhibitory effects of Wnt16 on Rankl-induced osteoclastogenesis. These results suggested that Wnt16 inhibited osteoclastogenesis, but not the function of osteoclasts and that Wnt16, an inhibitory Wnt ligand for osteoclastogenesis, regulates bone resorption in conjunction with Wnt5a.

The cytoskeletal organization of osteoclasts is required for bone resorption. Binding of dynamin with guanosine triphosphate (GTP) was previously suggested to be required for the organization of the actin cytoskeleton. However, the role of the GTPase activity of dynamin in the organization of the actin cytoskeleton as well as in the bone-resorbing activity of osteoclasts remains unclear. This study investigated the effects of dynasore, an inhibitor of the GTPase activity of dynamin, on the bone-resorbing activity of and actin ring formation in mouse osteoclasts in vitro and in vivo. Dynasore inhibited the formation of resorption pits in osteoclast cultures by suppressing actin ring formation and rapidly disrupting actin rings in osteoclasts. A time-lapse image analysis showed that dynasore shrank actin rings in osteoclasts within 30 min. The intraperitoneal administration of dynasore inhibited receptor activator of nuclear factor κB ligand (RANKL)-induced trabecular bone loss in mouse femurs. These in vitro and in vivo results suggest that the GTPase activity of dynamin is critical for the bone-resorbing activity of osteoclasts and that dynasore is a seed for the development of novel anti-resorbing agents.

In Japan, the installed capacity of Photovoltaic(PV) generation systems reached about 30GW in 2015, in which there would be surplus power in whole power system in light load season. In order to install the PV system without affecting stable operation of power system, the Japanese government set a new rule to restrict PV output when the surplus power occurred in whole power system. Authors has developed operation and planning method of customers' appliances for utilizing surplus power of PV at the customer's side. To apply the new rule to restrict PV output for the developed method, improvement of the developed operation and planning method is necessary. This paper develops the improved operation and planning method of customers' appliances considering the new rule for PV output restriction. The simulation analysis has been conducted to validate the developed method. Simulation results shows that proposed method can reduce the customer's electricity bill by 10–20%, restricted energy of PV output by 10–20% when the selling rate of PV output is 9.27yen/kWh, which shows validity of proposed method.

Cytoskeletal reorganization in osteoclasts to form actin rings is necessary for these cells to attach to bone and resorb bone matrices. We delineated the pathway through which Wnt5a signaling through receptor tyrosine kinase–like orphan receptor 2 (Ror2) promoted the bone-resorbing activity of osteoclasts. Wnt5a binding to Ror2 stimulated Rho, a small GTPase involved in cytoskeletal reorganization. Subsequently, the Rho effector kinase Pkn3 bound to and enhanced the activity of c-Src, a nonreceptor tyrosine kinase that is critical for actin ring formation. Mice with an osteoclast-specific deficiency in Ror2 ( Ror2 ΔOcl/ΔOcl ) had increased bone mass. Osteoclasts derived from these mice exhibited impaired bone resorption and actin ring formation, defects that were rescued by overexpression of constitutively active RhoA. These osteoclasts also exhibited reduced interaction between c-Src and Pkn3 and reduced c-Src kinase activity. Similar to Ror2 ΔOcl/ΔOcl mice, mice with a global deficiency of Pkn3 ( Pkn3 −/− ) had increased bone mass. The proline-rich region and kinase domain of Pkn3 were required to restore the bone-resorbing activity of osteoclasts derived from Pkn3 −/− mice. Thus, Pkn3 promotes bone resorption downstream of Wnt5a-Ror2-Rho signaling, and this pathway may be a therapeutic target for bone diseases such as osteoporosis, rheumatoid arthritis, and periodontal disease.

Bone formation is coupled to bone resorption throughout life. However, the coupling mechanisms are not fully elucidated. Using Tnfrsf11b-deficient (OPG

Body surface tissues, such as the oral cavity, contact directly with the external environment and are continuously exposed to microbial insults. Cathelicidins are a family of antimicrobial peptides that are found in mammalian species. Humans and mice have only one cathelicidin. Cathelicidins are expressed in a variety of surface tissues. In addition, they are abundantly expressed in bone and bone marrow. Infectious stimuli upregulate the expression of cathelicidins, which play sentinel roles in allowing the tissues to fight against microbial challenges. Cathelicidins disrupt membranes of microorganisms and kill them. They also neutralize microbe-derived pathogens, such as lipopolysaccharide (LPS) and flagellin. Besides their antimicrobial functions, cathelicidins can also control actions of host cells, such as chemotaxis, proliferation, and cytokine production, through binding to the receptors expressed on them. LPS and flagellin induce osteoclastogenesis and the production of cathelicidins, which can in turn inhibit osteoclastogenesis. Thus, cathelicidins contribute to maintaining microbiota-host homeostasis and promoting repair responses to inflammatory insults. In this review, we describe recent findings on the multiple roles of cathelicidins in host defense. We also discuss the significance of the human cathelicidin, LL-37, as a pharmaceutical target for the treatment of inflammation and bone loss in infectious diseases, such as periodontitis.

Colony-stimulating factor-1 (CSF-1) is widely expressed and considered to regulate the development, maintenance, and function of mononuclear phagocyte lineage cells such as monocytes, macrophages, dendritic cells (DCs), Langerhans cells (LCs), microglia, and osteoclasts. Interleukin-34 (IL-34) was recently identified as an alternative ligand for the CSF-1 receptor (CSF-1R) through functional proteomics experiments. It is well established that the phenotype of CSF-1R-deficient (CSF-1R⁻/⁻) mice is more severe than that of mice bearing a spontaneous null mutation in CSF-1 (CSF-1(op/op)). CSF-1R⁻/⁻ mice are severely depleted of macrophages and completely lack LCs, microglia, and osteoclasts during their lifetime. In contrast, CSF-1(op/op) mice exhibit late-onset macrophage development and osteoclastogenesis, whereas they show modestly reduced numbers of microglia and a relatively normal LC development. In contrast, IL-34-deficient (IL-34⁻/⁻) mice show a marked reduction of LCs and a decrease in microglia. IL-34 and CSF-1 display different spatiotemporal expression patterns and have distinct biological functions. In this review, we focus on the functional similarities and differences between IL-34 and CSF-1 in vivo.

Measured data from IT switches are utilized in order to control voltage in Japanese distribution systems with photovoltaic generation systems. However, length of period from the data measurement to the data acquisition from IT switches by SCADA affects voltage control ability in a distribution automation system. In this paper, the effect of the length of the data acquisition period for voltage control by LRT and SVR is evaluated through numerical simulations in a distribution system model. Furthermore, the optimal length of the data acquisition period is determined according to PV penetration rate.

Tetracyclines such as doxycycline and minocycline are used to suppress bacterial growth in patients with inflammatory diseases. Tetracyclines have been shown to prevent bone loss, but the underlying mechanisms are unknown. Osteoclasts and dendritic cells (DCs) are derived from common progenitors such as bone marrow-derived macrophages (BMMs). Here, we showed that minocycline converts the differentiation pathway, which results in DC-like cells and not osteoclasts. Minocycline inhibited the receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis of BMMs but had no effects on cell growth and phagocytic activity. It influenced neither the proliferation nor differentiation of bone-forming osteoblasts. Surprisingly, minocycline induced the expression of DC markers, CD11c and CD86, in BMMs in the presence of RANKL. STAT5 is involved in DC differentiation that is induced by granulocyte–macrophage colony-stimulating factor (GM-CSF). Midostaurin, which is a STAT5 signaling inhibitor and an anti-GM-CSF neutralizing antibody, suppressed the differentiation that was induced by GM-CSF but not by tetracyclines. In vivo, the injection of minocycline into RANKL-injected mice and RANKL-transgenic mice suppressed RANKL-induced osteoclastogenesis and promoted the concomitant appearance of CD11c-positive cells. These results suggest that minocycline prevents bone loss that is induced by local inflammation, including rheumatoid arthritis and periodontitis, through osteoclast-DC-like cell conversion.

Periodontitis, an inflammatory disease of periodontal tissues, is characterized by excessive alveolar bone resorption. An increase in the receptor activator of nuclear factor-κB ligand (RANKL) to osteoprotegerin (OPG) ratio is thought to reflect the severity of periodontitis. Here, we examined alveolar bone loss in OPG-deficient (OPG−/−) mice and RANKL-overexpressing transgenic (RANKL-Tg) mice. Alveolar bone loss in OPG−/− mice at 12 weeks was significantly higher than that in RANKL-Tg mice. OPG−/− but not RANKL-Tg mice exhibited severe bone resorption especially in cortical areas of the alveolar bone. An increased number of osteoclasts was observed in the cortical areas in OPG−/− but not in RANKL-Tg mice. Immunohistochemical analyses showed many OPG-positive signals in osteocytes but not osteoblasts. OPG-positive osteocytes in the cortical area of alveolar bones and long bones were abundant in both wild-type and RANKL-Tg mice. This suggests the resorption in cortical bone areas to be prevented by OPG produced locally. To test the usefulness of OPG−/− mice as an animal model for screening drugs to prevent alveolar bone loss, we administered an antimouse RANKL antibody or risedronate, a bisphosphonate, to OPG−/− mice. They suppressed alveolar bone resorption effectively. OPG−/− mice are useful for screening therapeutic agents against alveolar bone loss.

In recent years, the capacity of installed distributed energy resources (DERs) using renewable energy such as photovoltaic systems (PVs) has been increasing. In the near future, battery energy storage systems (BESs) may also be installed. Then, smart communities using DERs and BESs are expected to realize the efficient use of energy in demand area. However, if the smart communities are operated to optimize their local objectives (cost minimization, etc.), the demand fluctuations of the communities will be complicated. Then, there may be problems in the distribution system, such as voltage rise and overcurrent. In this study, simulation models to evaluate the mutual impact between a smart community and a distribution system are proposed, and the impact of the autonomous operation of a smart community using BESs on the distribution system is evaluated by the simulation analyses.

Long-term treatment with active vitamin D [1α,25(OH)

In mammalian assay systems, calcitonin peptides of non-mammalian species exhibit stronger activity than those of mammals. Recently, comparative analyses of a wide-range of species revealed that platypus and opossum, which diverged early from other mammals, possess calcitonins that are more similar in amino acid sequence to those of non-mammals than mammals. We herein determined whether platypus and opossum calcitonins exhibit similar biological activities to those of non-mammalian calcitonins using an assay of actin ring formation in mouse osteoclasts. We also compared the dose-dependent effects of each calcitonin on cAMP production in osteoclasts. Consistent with the strong similarities in their primary amino acid sequences, platypus and opossum calcitonins disrupted actin rings with similar efficacies to that of salmon calcitonin. Human calcitonin exhibited the weakest inhibitory potency and required a 100-fold higher concentration (EC50=3×10-11M) than that of salmon calcitonin (EC50=2×10-13M). Platypus and opossum calcitonins also induced cAMP production in osteoclast cultures with the same efficacies as that of salmon calcitonin. Thus, platypus and opossum calcitonins exhibited strong biological activities, similar to those of the salmon. In addition, phylogenetic analysis revealed that platypus and opossum calcitonins clustered with the salmon-type group but not human- or porcine-type group. These results suggest that platypus and opossum calcitonins are classified into the salmon-type group, in terms of the biological activities and amino acid sequences.