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Brain-derived neurotrophic factor (BDNF) is expressed in both hypothalamic neurons and microglia, and plays a critical role in the regulation of metabolism. Although hypothalamic expression of BDNF is regulated by metabolic signals such as nutrients and hormones, it remains unknown whether these signals differentially regulate BDNF expression in different cell types. The present study aimed to determine whether glucose and fructose regulate BDNF expression in microglia via the specific glucose transporter. To determine the effect of glucose and fructose on Bdnf mRNA and protein expression, murine microglial cell line SIM-A9 cells were exposed to the maintenance concentration of glucose (17.5 mmol/l), high glucose (25 mmol/l), or fructose (7.5 mmol/l) for 40 min to 24 h. To determine whether the blockade of glucose transporter 5 (GLUT5) negates the effect of glucose on Bdnf mRNA expression, cells were exposed to 25 mmol/l glucose in the presence or absence of the GLUT5 inhibitor for 4 h. Levels of Bdnf mRNA and protein were measured by real-time PCR and ELISA, respectively. High glucose caused a significant increase in both pan-Bdnf and long-form Bdnf (L-Bdnf) mRNA as well as protein levels when compared with the maintenance of concentration of glucose in a time-dependent manner. Fructose treatment also increased L-Bdnf mRNA expression. Pharmacological blockade of GLUT5 did not affect glucose-induced Bdnf mRNA expression. These findings suggest that glucose and fructose directly stimulate Bdnf mRNA expression in microglia and these responses may mediate the metabolic actions of glucose and fructose.

Feeding-regulating neurotrophic factors are expressed in both neurons and glial cells. However, nutritional regulation of anorexigenic glial cell line-derived neurotrophic factor (GDNF) and orexigenic mesencephalic astrocyte-derived neurotrophic factor (MANF) expression in specific cell types remains poorly understood. Hypothalamic glucose sensing plays a critical role in the regulation of food intake. It has been theorized that local glucose concentration modulates microglial activity partially via glucose transporter 5 (GLUT5). We hypothesized that an increased local glucose concentration stimulates GDNF expression while inhibiting MANF expression in the hypothalamus and microglia via GLUT5. The present study investigated the effect of glucose on Gdnf and Manf mRNA expression in the mouse hypothalamus and murine microglial cell line SIM-A9. Intracerebroventricular glucose treatment significantly increased Gdnf mRNA levels in the hypothalamus without altering Manf mRNA levels. Exposure to high glucose caused a significant increase in Gdnf mRNA expression and a time-dependent change in Manf mRNA expression in SIM-A9 cells. GLUT5 inhibitor treatment did not block glucose-induced Gdnf mRNA expression in these cells. These findings suggest that microglia are responsive to changes in the local glucose concentration and increased local glucose availability stimulates the expression of microglial GNDF through a GLUT5-independent mechanism, contributing to glucose-induced feeding suppression.

We herein report that a copper-ion-exchanged erionite zeolite (Cu-ERI) exhibited a methanol yield as high as 147 μmol/g-zeolite, equaling 0.224 μmol/μmol-Cu, in the direct oxidation of methane to m...

M87 has been the target of numerous astronomical observations across the electromagnetic spectrum, and very long baseline interferometry has resolved an edge-brightened jet(1-4). However, the origin and formation of its jets remain unclear. In our current understanding, black holes (BH) are the driving engine of jet formation(5), and indeed the recent Event Horizon Telescope observations revealed a ring-like structure in agreement with theoretical models of accretion onto a rotating Kerr BH6. In addition to the spin of the BH being a potential source of energy for the launching mechanism, magnetic fields are believed to play a key role in the formation of relativistic jets(7,8). A priori, the spin, a(*), of the BH in M87* is unknown; however, when accounting for the estimates of the X-ray luminosity and jet power, values of vertical bar a(*)vertical bar greater than or similar to 0.5 appear favoured(6). Besides the properties of the accretion flow and the BH spin, the radiation microphysics including the particle distribution (thermal(6) and non-thermal(9,10)) as well as the particle acceleration mechanism(11) play a crucial role. We show that general relativistic magnetohydrodynamic simulations and general relativistic radiative transfer calculations can reproduce the broadband spectrum from the radio to the near-infrared regime and simultaneously match the observed collimation profile of M87, thus allowing us to set rough constraints on the dimensionless spin of M87* to be 0.5 less than or similar to a(*) less than or similar to 1.0, with higher spins being possibly favoured.

Microglia play a role in the regulation of metabolism and pathogenesis of obesity. Microglial activity is altered in response to changes in diet and the body’s metabolic state. Solute carrier family 2 member 5 (Slc2a5) that encodes glucose transporter 5 (GLUT5) is a fructose transporter primarily expressed in microglia within the central nervous system. However, little is known about the nutritional regulation of Slc2a5 expression in microglia and its role in the regulation of metabolism. The present study aimed to address the hypothesis that nutrients affect microglial activity by altering the expression of glucose transporter genes. Murine microglial cell line SIM-A9 cells and primary microglia from mouse brain were exposed to different concentrations of glucose and levels of microglial activation markers and glucose transporter genes were measured. High concentration of glucose increased levels of the immediate-early gene product c-Fos, a marker of cell activation, Slc2a5 mRNA, and pro-inflammatory cytokine genes in microglial cells in a time-dependent manner, while fructose failed to cause these changes. Glucose-induced changes in pro-inflammatory gene expression were partially attenuated in SIM-A9 cells treated with the GLUT5 inhibitor. These findings suggest that an increase in local glucose availability leads to the activation of microglia by controlling their carbohydrate sensing mechanism through both GLUT5-dependent and –independent mechanisms.

Context Abnormally increased hepatic glucose production contributes to hyperglycemia in diabetes. Interventions that suppress hepatic gluconeogenesis should be beneficial in improving glycemic control in patients with diabetes. Objectives It has been suggested that hepatic FTO is involved in glycemic control by regulating gluconeogenesis. Both FTO and activating transcription factor 4 (ATF4) positively regulate the expression of gluconeogenic genes in the liver, suggesting the possibility that ATF4 mediates the stimulatory effect of FTO on hepatic gluconeogenesis. The present study aimed to determine the effect of altered expression or activity of FTO on Atf4 and gluconeogenic gene expression in hepatocyte cells. Methods Mouse hepatocyte AML12 cells were treated with the FTO inhibitor rhein or transfected with an FTO-expressing plasmid. Levels of gluconeogenic glucose-6-phosphatase (G6pc) and Atf4 mRNA and protein were measured. Results Rhein treatment significantly reduced G6pc mRNA levels as well as Atf4 mRNA and protein levels. Conversely, enhanced FTO expression caused an increase in G6pc and Atf4 mRNA levels. Conclusions These findings support the hypothesis that hepatic FTO participates in the regulation of hepatic gluconeogenic gene and ATF4 expression. Reducing the activity of the hepatic FTO-ATF4 pathway may be beneficial in reducing hepatic glucose production and ameliorating hyperglycemia in diabetes.

Social and environmental factors influence behavior via modulation of brain physiological functions. Environmental enrichment (EE) is an animal housing technique that provides complex sensory, motor, and social stimulation, leading to modifications in the innate aggressiveness in group-housed laboratory mice. Brain-derived neurotrophic factor (BDNF) is encoded by multiple splice variants and plays a critical role in controlling aggressive behavior in a transcript variant-specific manner. BDNF mediates the beneficial effects of EE on a variety of pathophysiological conditions. These findings led to the hypothesis that EE reduces aggressive behavior by altering the expression of Bdnf mRNA in a transcript variant-specific manner. To test this hypothesis, 3-4-week-old male C57BL/6 mice were randomly group-housed (5 mice per cage) under standard or EE conditions for 6-8 weeks. Aggressive behavior was monitored and levels of Bdnf mRNA variants in aggression-related brain regions were measured. Mice housed in EE cages displayed a significantly lower frequency of aggressive interactions compared to control mice. EE increased levels of Bdnf mRNA variant I (Bdnf I) in the amygdala while it reduced levels of Bdnf I in the hypothalamus, hippocampus, prefrontal cortex, parietal cortex, and brainstem. Meanwhile, EE did not significantly alter levels of Bdnf mRNA variants IIc, IV, and VI in all brain regions examined. These findings support the hypothesis that EE diminishes inter-male aggression by altering Bdnf mRNA expression in a transcript variant-specific and brain region-specific manner. Specifically, brain region-specific alterations in Bdnf I expression may partly mediate EE-induced suppression of inter-male aggression.

The isothermal, low-temperature stepwise conversion of methane to methanol over copper-exchanged zeolites eliminates the time-consuming heating and cooling steps of the conventional high temperature activation approach. To better understand differences between the two approaches, a series of zeolites were screened, of which omega zeolite (MAZ) showed superior performance in both the isothermal and conventional approaches.

Our understanding of strong gravity near supermassive compact objects has recently improved thanks to the measurements made by the Event Horizon Telescope (EHT). We use here the M87∗ shadow size to infer constraints on the physical charges of a large variety of nonrotating or rotating black holes. For example, we show that the quality of the measurements is already sufficient to rule out that M87∗ is a highly charged dilaton black hole. Similarly, when considering black holes with two physical and independent charges, we are able to exclude considerable regions of the space of parameters for the doubly-charged dilaton and the Sen black holes. © 2021 authors. Published by the American Physical Society.

JLab E12-19-002 Experiment is planned to measure the Λ-binding energies of 3ΛH [Jπ = 1/2+ or 3/2+(T = 0)] and 4ΛH (1+) at JLab Hall C. The expected accuracy for the binding-energy measurement is |ΔBtotal Λ | ≃ 70 keV. The accurate spectroscopy for these light hypernuclei would shed light on the puzzle of the small binding energy and short lifetime of 3ΛH, and the chargesymmetry breaking in the ΛN interaction. We aim to perform the experiment in 2025.

Objectives As new medical technology develops, medical costs increase. When high medical costs affect the patient as a toxicity, it is called financial toxicity (FT). In Japan, all patients are covered by the public health insurance system, which may alleviate FT. However, previous research using the Japanese version of the ‘‘‘‘‘COmprehensive Score for financial Toxicity (COST)’’’’’ tool, whose score quantifies FT, showed that Japanese patients with cancer had FT. Our objective is to analyze its internal validity and the relationship between the COST score and patient information particularly for patients with ovarian, cervical, or endometrial cancer during chemotherapy. Furthermore, this study aims to clarify the correlation between COST and QOL scores. Methods We will enroll 147 patients, including 49 patients each with ovarian, cervical, and endometrial cancers, from April 2019 to April 2020. Each patient will have been receiving chemotherapy for more than 2 months at enrollment. Each participant will answer the COST tool, EORTC-QLQ-C30, OV28/CX24/EN24, and EQ-5D-5L at baseline and at the end of chemotherapy. The patients will also complete a questionnaire about employment, assets, income, private insurance, medical payments in the last 2 months, presence of children or family members who need a caregiver, and consultation for medical payment before chemotherapy. Results This research will clarify the characteristics and longitudinal changes in the COST score in gynecologic cancer patients. The impact of FT on the clinical situation will also be determined. Conclusions We expect to find that the COST score can be used prospectively to improve QOL in patients with gynecologic cancer.

Hepatic metabolism is critical for the maintenance of whole body glucose and lipid metabolism. Excessive hepatic glucose production and de novo lipogenesis contributes to fasting hyperglycemia in diabetes and hepatic steatosis, respectively. Common genetic variants of the fat mass and obesity associated (FTO) gene are strongly associated with obesity and type 2 diabetes. However, the role of FTO in the regulation of hepatic metabolism is not well understood. We have demonstrated that increased FTO level leads to an increase in gluconeogenic glucose-6-phosphatase (G6Pase) mRNA expression in hepatic cells. Conversely, reduced FTO level or inhibition of FTO activity caused a reduction of G6Pase mRNA expression. The transcription factor activating transcription factor 4 (ATF4) is a positive regulator of the expression of gluconeogenic and lipogenic genes in hepatocytes. These findings led to the hypothesis that increased hepatic FTO expression or activity leads to an increase expression of not only gluconeogenic genes but also lipogenic genes by activating ATF4, while reduced hepatic FTO expression or activity produces opposite effects. To address this hypothesis, we examined the effect of altered FTO expression on ATF4 and lipogenic stearoyl-CoA desaturase (SCD1) mRNA levels in alpha mouse liver 12 (AML12) immortalized hepatic cell line. We also treated AML12 cells with a small molecule FTO inhibitor rhein and measured the expression level of these genes. FTO overexpression resulted in increased ATF4 and SCD1 mRNA levels. FTO knockdown resulted in a reduction of SCD1 mRNA levels. Similarly, rhein treatment (1 μM) for 24 h reduced levels of ATF4 and SCD1 mRNA without causing cytotoxicity. These data support the hypothesis that FTO acts to shift hepatic metabolism toward anabolism, leading to increased gluconeogenesis and de novo lipogenesis and ATF4 is a possible mediator of this action. Our data also suggest that reduced activity of hepatic signaling pathways involving FTO and ATF4 may be effective in reversing hyperglycemic and hepatic steatosis partly by reducing gluconeogenesis and de novo lipogenesis in the liver. Sources of Research Support: Supported by University Research Grants Program (URGP) from University of Manitoba.

The hypothalamus controls food intake and metabolism by integrating nutrient and hormonal signals from peripheral tissues. Both central and peripheral administration of glucose leads to a reduction in food intake in rodents. Similarly, administration of the adipocyte hormone leptin or the gastrointestinal hormone xenin reduces food intake. In contrast, impairments in hypothalamic signaling of these factors cause hyperphagia and obesity in rodents and humans. Environmental factors affect behavior including feeding behavior and energy metabolism in rodents and humans. Studies have found that environmental enrichment (EE), in which mice interact with complex sensory and motor stimulation, led to a significant reduction in adiposity and resistance to diet-induced obesity in mice. This effect is independent of energy expenditure and is associated with enhanced hypothalamic signaling, but the exact mechanism is unknown. We hypothesized that EE potentiates the feeding suppressing effects of anorectic signals. To address this hypothesis, 4-week-old male C57BL/6 mice were group housed (5/cage) under standard laboratory conditions or EE conditions with free access to regular rodent chow and feeding response to glucose, leptin and xenin was examined. EE cages were supplemented with a house, running wheels, igloos, wood logs, maze and nesting materials. Four weeks after initiating EE protocol, mice were fasted for 8 h and received an intraperitoneal injection of glucose (2 mg/g b.w.) or saline just before the onset of the dark phase. Treatment assignments were reversed for the second injection so that each animal received both treatments with a washout period of 1 week. Mice were given food immediately after the injection and food intake was measured for 4 h after the injection at 0.5–1 h intervals. The same design was repeated using leptin (2.5 μg/g b.w.) and xenin (15 or 50 μg/g b.w.). Glucose injection caused a significant reduction of food intake in both control and EE mice. However, anorexic effect of glucose was more significant in EE group compared to the control group (main effect of treatment: P = 0.0016 for control and P < 0.0001 for EE, two-way ANOVA). Significant reductions in food intake were observed between 0.5 and 2.5 h after glucose injection in EE mice, while no significant reduction was observed thereafter. Moreover, three-way ANOVA showed a significant interaction between housing condition and treatment (P = 0.0086). In contrast, although both leptin and xenin caused a significant reduction in food intake, there was no significant interaction between housing condition and treatment. These data suggest that environmental enrichment enhances the anorectic action of glucose without altering feeding response to leptin and xenin. It is speculated that enhanced hypothalamic glucose sensing may mediate beneficial effects of environmental enrichment on metabolism.

Xenin is a gut hormone that reduces food intake by partly acting through the hypothalamus via neurotensin receptor 1 (Ntsr1). However, specific signaling pathways that mediate xenin-induced feeding suppression are not fully understood. Activation of Ntsr1 leads to the activation of the extracellular signal-regulated kinase (ERK). Hypothalamic ERK participates in the regulation of food intake by mediating the effect of hormonal signals. Therefore, we hypothesized that the anorectic effect of xenin is mediated by hypothalamic ERK signaling. To address this hypothesis, we compared levels of phosphorylation of ERK1/2 (pERK1/2) in the hypothalamus of both control and xenin-treated mice. The effect of xenin on ERK1/2 phosphorylation was also examined in mouse hypothalamic neuronal cell lines with or without Ntsr1. We also examined the effect of the blockade of central ERK signaling on xenin-induced feeding suppression in mice. The intraperitoneal (i.p.) injection of xenin caused a significant increase in the number of pERK1/2-immunoreactive cells in the hypothalamic arcuate nucleus. The majority of pERK1/2-positive cells expressed neuronal nuclei (NeuN), a marker for neurons. Xenin treatment increased pERK1/2 levels in one cell line expressing Ntsr1 but not another line without Ntsr1 expression. Both i.p. and intracerebroventricular (i.c.v.) injections of xenin reduced food intake in mice. The i.c.v. pre-treatment with U0126, a selective inhibitor of ERK1/2 upstream kinases, did not affect xenin-induced reduction in food intake. These findings suggest that although xenin activates ERK signaling in subpopulations of hypothalamic neurons, xenin does not require the activation of hypothalamic ERK signaling pathway to elicit feeding suppression.

We developed a membrane-lytic peptide (LP) having 26 amino acid residues composed of a helix-promoting hydrophobic segment (Leu-Ala repetitive sequence) and a cationic segment from melittin. In the presence of liposomes, LP interacts with liposomal surfaces to form a hydrophobic helix in the lipid bilayer in a wide pH range. In order to provide LP with a weakly acidic (endosomal) pH-controlled membrane-lytic activity, we have designed an LPE peptide series (a typical peptide, LPE3-1) with a hydrophobic segment in which Leu (L) residues are replaced by acidic Glu (E) residues. To analyze the pH-selective membrane-lytic activity of the designed peptides, both calcein leakage and membrane accessibility assays were performed. In the case of membrane disruption induced by the active pore formation, the incorporated calcein would leak from the liposomes and simultaneously the aqueous solution in the membrane surrounding would be accessible to the liposome interior at pH 5.0. The assays in the presence of LPE3-1 indicated no significant leakage or accessibility at pH 7.4, but a typical leakage and some accessibility to liposomes were positively observed at pH 5.0. In order to estimate whether the weakly acidic pH-controlled lytic activity is due to a secondary structural change of the hydrophobic segment of LPE3-1 in the liposome membrane, we have measured circular dichroism spectra. In the presence of liposomes, the minimum showing the characteristic helical structure was observed at 222 nm only under weakly acidic conditions. This pH dependence is in good agreement with the results from the leakage and accessibility assays. The pH-dependent membrane disruption properties of LPE3-1 may open a new avenue to gain insight into the interaction between peptides and lipids for the development of efficient drug/gene delivery systems.

Xenin is a gastrointestinal hormone that belongs to the neurotensin family. Central administration of xenin to obese mice reduces food intake and body weight gain and causes alterations in the expression of lipid metabolism-related genes and proteins in white adipose tissue (WAT). However, it has not been tested whether or not xenin directly acts on adipose tissue and alters lipid metabolism. The present study was performed to address this possibility by examining the effect of xenin treatment on the levels of glycerol and free fatty acids (FFA) and expression levels of lipolysis marker proteins ex vivo in cultured mouse WAT. Xenin treatment significantly increased concentrations of glycerol and FFA in culture media and increased phosphorylation of hormone sensitive lipase (HSL) in ex vivo cultured WAT. These findings support the hypothesis that xenin directly acts on adipose tissues and stimulates lipolysis. Thus, enhancement of xenin action and its downstream signaling may offer a novel and effective therapy for obese patients by reducing the amount of stored fat in adipose tissue.

Background A single-arm confirmatory trial (JCOG1101) is now on follow-up, which is to evaluate the efficacy of modified radical hysterectomy for FIGO Stage IB1 uterine cervical cancer patients (pts) with clinical maximal tumor diameter (MTD) estimated 2 cm or less (UMIN-CTR: UMIN000009726). It is needed to evaluate whether application of modified radical hysterectomy is feasible or not. Methods From Jan 2013 to Aug 2017, 240 pts were enrolled. We analyzed the data of 224 eligible pts who underwent modified radical hysterectomy to elucidate the relationship between clinical maximal tumor diameter (cMTD) and pathological MTD (pMTD), degree of tumor extension and adverse events (AEs). Results In 224 eligible pts, median pMTD was 1.5 cm (range, 0-4.5), and. pMTD were Conclusions Though cMTD does not always correspond to pMTD on stage IB1 cervical cancer, low incidence of parametrial involvement and lymph node metastasis indicate that cMTD is useful as presurgical diagnosis. In addition, there was low frequency of AEs by modified radical hysterectomy, which was presumed to be less invasive than radical hysterectomy. Modified radical hysterectomy will be a standard surgery if the efficacy of modified radical hysterectomy in overall survival is confirmed by the primary analysis planned in 2022. Clinical trial identification UMIN-CTR: UMIN000009726, 08/Jan/2013. Legal entity responsible for the study JCOG (Japan Clinical Oncology Group). Funding National Cancer Center Research and Development Funds. Disclosure All authors have declared no conflicts of interest.

Debilitating muscle-disuse atrophy in aging or obesity has huge socioeconomic impact. Since nitric oxide (NO) mediates muscle satellite cell activation and induces hypertrophy with exercise in old mice, we tested whether treatment with the NO donor, isosorbide dinitrate (ISDN), during hind limb suspension would reduce atrophy. Mice were suspended 18 days, with or without daily ISDN (66 mg/kg). Muscles were examined for atrophy (weight, fiber diameter); regulatory changes in atrogin-1 (a negative regulator of muscle mass), myostatin (inhibits myogenesis), and satellite cell proliferation; and metabolic responses in myosin heavy chains (MyHCs), liver lipid, and hypothalamic gene expression. Suspension decreased muscle weight and weight relative to body weight between 25–55%, and gastrocnemius fiber diameter vs. controls. In young-adult mice, ISDN attenuated atrophy by half or more. In quadriceps, ISDN completely prevented the suspension-induced rise in atrogin-1 and drop in myostatin precursor, and attenuated the changes in MyHCs 1 and 2b observed in unloaded muscles without treatment. Fatty liver in suspended young-adult mice was also reduced by ISDN; suspended young mice had higher hypothalamic expression of the orexigenic agouti-related protein, Agrp than controls. Notably, a suspension-induced drop in muscle satellite cell proliferation by 25–58% was completely prevented (young mice) or attenuated (halved, in young-adult mice) by ISDN. NO-donor treatment has potential to attenuate atrophy and metabolic changes, and prevent regulatory changes during disuse and offset/prevent wasting in age-related sarcopenia or space travel. Increases in precursor proliferation resulting from NO treatment would also amplify benefits of physical therapy and exercise.

Two high-speed video cameras are successfully used to detect the motion of a flying shuttlecock of badminton. The shuttlecock detection system is applied to badminton robots that play badminton fully autonomously. The detection system measures the three dimensional position and velocity of a flying shuttlecock, and predicts the position where the shuttlecock falls to the ground. The badminton robot moves quickly to the position where the shuttle-cock falls to, and hits the shuttlecock back into the opponent’s side of the court. In the game of badminton, there is a large audience, and some of them move behind a flying shuttlecock, which are a kind of background noise and makes it difficult to detect the motion of the shuttlecock. The present study demonstrates that such noises can be eliminated by the method of stereo imaging with two high-speed cameras.

The cross sections of the $^{7}\mathrm{Be}(n,\ensuremath{\alpha})^{4}\mathrm{He}$ reaction for $p$-wave neutrons were experimentally determined at ${E}_{\mathrm{c}.\mathrm{m}.}=0.20--0.81\text{ }\text{ }\mathrm{MeV}$ slightly above the big bang nucleosynthesis (BBN) energy window for the first time on the basis of the detailed balance principle by measuring the time-reverse reaction. The obtained cross sections are much larger than the cross sections for $s$-wave neutrons inferred from the recent measurement at the n_TOF facility in CERN, but significantly smaller than the theoretical estimation widely used in the BBN calculations. The present results suggest the $^{7}\mathrm{Be}(n,\ensuremath{\alpha})^{4}\mathrm{He}$ reaction rate is not large enough to solve the cosmological lithium problem, and this conclusion agrees with the recent result from the direct measurement of the $s$-wave cross sections using a low-energy neutron beam and the evaluated nuclear data library ENDF/B-VII.1.

Xenin is a gastrointestinal hormone that reduces food intake when administered centrally and it has been hypothesized that central action of xenin participates in the regulation of whole-body metabolism. The present study was performed to address this hypothesis by investigating the central effect of xenin on the expression of genes and proteins that are involved in the regulation of lipid metabolism in white adipose tissue (WAT). Male obese ob/ob mice received intracerebroventricular (i.c.v.) injections of xenin (5μg) twice 12h apart. Food intake and body weight change during a 24-h period after the first injection were measured. Epididymal WAT was collected at the end of the 24-h treatment period and levels of lipid metabolism-related genes and proteins were measured. Xenin treatment caused significant reductions in food intake and body weight compared to control vehicle treatment. Levels of fatty acid synthase (FASN) protein were significantly reduced by xenin treatment, while levels of adipose triglyceride lipase (Atgl) and beta-3 adrenergic receptor (Adrb3) mRNA and phosphorylated hormone sensitive lipase (Ser660-pHSL and Ser563-pHSL) were significantly increased by xenin treatment. These findings suggest that central action of xenin causes alterations in lipid metabolism in adipose tissue toward reduced lipogenesis and increased lipolysis, possibly contributing to xenin-induced body weight reduction. Thus, enhancing central action of xenin and its downstream targets may be possible targets for the treatment of obesity by reducing the amount of stored fat in adipose tissue.

Current surgical intervention of craniofacial defects caused by injuries or abnormalities uses reconstructive materials, such as autologous cartilage grafts. Transplantation of autologous tissues, however, places a significant invasiveness on patients, and many efforts have been made for establishing an alternative graft. Recently, we and others have shown the potential use of reconstructed elastic cartilage from ear-derived chondrocytes or progenitors with the unique elastic properties. Here, we examined the differentiation potential of canine joint cartilage-derived chondrocytes into elastic cartilage for expanding the cell sources, such as hyaline cartilage. Articular chondrocytes are isolated from canine joint, cultivated, and compared regarding characteristic differences with auricular chondrocytes, including proliferation rates, gene expression, extracellular matrix production, and cartilage reconstruction capability after transplantation. Canine articular chondrocytes proliferated less robustly than auricular chondrocytes, but there was no significant difference in the amount of sulfated glycosaminoglycan produced from redifferentiated chondrocytes. Furthermore, in vitro expanded and redifferentiated articular chondrocytes have been shown to reconstruct elastic cartilage on transplantation that has histologic characteristics distinct from hyaline cartilage. Taken together, cultured hyaline cartilage-derived chondrocytes are a possible cell source for elastic cartilage reconstruction.

ObjectivesIn order to ensure safety of the cell-based therapy for bone regeneration, we examined in vivo biodistribution of locally or systemically transplanted osteoblast-like cells generated from bone marrow (BM) derived mononuclear cells.MethodsBM cells obtained from a total of 13 Sprague-Dawley (SD) green fluorescent protein transgenic (GFP-Tg) rats were culture-expanded in an osteogenic differentiation medium for three weeks. Osteoblast-like cells were then locally transplanted with collagen scaffolds to the rat model of segmental bone defect. Donor cells were also intravenously infused to the normal Sprague-Dawley (SD) rats for systemic biodistribution. The flow cytometric and histological analyses were performed for cellular tracking after transplantation.ResultsLocally transplanted donor cells remained within the vicinity of the transplantation site without migrating to other organs. Systemically administered large amounts of osteoblast-like cells were cleared from various organ tissues within three days of transplantation and did not show any adverse effects in the transplanted rats.ConclusionsWe demonstrated a precise assessment of donor cell biodistribution that further augments prospective utility of regenerative cell therapy. Cite this article: Bone Joint Res 2014;3:76–81.

Expressway companies in Japan have developed middle performance concrete that uses stone powder and coal ash and compiled Construction Management Guidelines for it in August 2008. Stone powder and coal ash, however, do not satisfy the standard specifications for middle performance concrete owing to various factors including current distribution conditions and plant facility limitations. The authors, therefore, conducted studies to verify the properties and quality of middle performance concrete, using an admixture whose quality and availability do not depend on local conditions and reached a conclusion that such concrete is applicable as a standard material for highway tunnels. Furthermore, to evaluate the long-term durability of middle performance concrete, the authors also carried out a follow-up study of the middle performance concrete that uses coal ash and limestone fines, after construction, and found the concrete to be of greater density and higher quality than ordinary lining concrete.高速道路会社は，石粉や石炭灰を用いた中流動覆工コンクリートを開発し，平成20年8月に施工管理要領を制定した。しかし，石粉や石炭灰については，流通事情やプラントの設備の都合から，中流動覆工コンクリートの標準化には至っていない。そこで，現地条件に左右されない混和剤を用いた中流動覆工コンクリートの性状および品質確認を行い，高速道路トンネルへの標準仕様としての適用が可能であるとの結論を得た。また，中流動覆工コンクリートの長期耐久性検証のため，石炭灰および石灰石微粉末を用いた中流動覆工コンクリートの施工後からの追跡調査についても実施し，従来の覆工コンクリートよりも密実で高品質な状態であることを確認した。

The incidence of type 2 diabetes mellitus (T2DM) is increasing at an alarming rate. Insulin secretory dysfunction and insulin resistance are characteristic features of T2DM. However, their relative contributions to the progression from normal glucose tolerance to impaired glucose tolerance (IGT) to T2DM remain unknown. This limits the capacity of researchers to establish therapeutic interventions for T2DM. Glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 are the two primary incretin hormones secreted by intestinal K and L cells, respectively. Secretion of these incretins increases postprandially and they potentiate glucose-stimulated insulin secretion (GSIS). Despite blunted incretin responses in patients with T2DM, insulinotropic responses to exogenously administered GLP-1 remain active in these patients (1). Although controversy exists, a recent study demonstrated that insulin secretory responses to GIP were retained in patients with T2DM (1,2). Additionally, incretin response to GIP is improved by reducing blood glucose levels in patients with T2DM (3). These findings support the rationale for use of incretin-based pharmacotherapies in the treatment and management of T2DM. However, identification of the mechanism by which the function of K cells contributes to the development of T2DM is still elusive and requires a good model of study. To determine the role of K cells in the regulation of metabolism, K cells were eliminated from mice by expressing the diphtheria toxin A-chain gene in GIP-producing cells (DT mice). Despite a severely impaired …

Hypothalamic glucose sensing plays a critical role in the regulation of food intake and metabolism. Glucose injection, either centrally or peripherally suppresses food intake. However, the mechanism of glucose-induced feeding suppression is not fully understood. It has been demonstrated that hypothalamic interleukin 1 beta (IL-1β) mRNA levels are altered by metabolic states and IL-1 signaling participates in the regulation of food intake. Therefore, we hypothesized that hypothalamic IL-1 gene expression is regulated by glucose and glucose-induced feeding suppression is mediated via hypothalamic IL-1 signaling. To address this hypothesis, we examined the effect of glucose on IL-1α and IL-1β mRNA expression in the hypothalamus. We also examined the effect of intraperitoneal injection of glucose on food intake in wild-type and type I IL-1 receptor (IL-1RI)-deficient mice. Levels of IL-1α and IL-1β mRNA in the hypothalamus were increased in response to feeding and intraperitoneal injection of glucose, and were positively correlated with blood glucose levels in mice. Exposure of hypothalamic explants to high glucose (10 mM) media increased IL-1α and IL-1β mRNA levels compared to low glucose (1 mM) media. Intraperitoneal glucose administration reduced food intake in wild-type mice, while the feeding-suppressing effect of glucose was attenuated in IL-1RI-deficient mice. These findings support the role for hypothalamic IL-1 signaling in the mediation of the anorectic effect of glucose.

Aims To investigate the role of glucose and insulin in the regulation of hepatic fat mass and obesity associated ( Fto ) gene expression and the role of hepatic Fto in the regulation of gluconeogenic gene expression. Main methods To determine the effect of hyperglycemia on hepatic Fto expression, levels of Fto mRNA in liver were compared between normoglycemic/normoinsulinemic, hypereglycemic/hyperinsulinemic, and hyperglycemic/hypoinsulinemic mice. To determine the direct effect of insulin on Fto expression, levels of Fto , glucose-6-phosphatase ( G6pase ), and phosphoenolpyruvate carboxykinase ( Pepck ) mRNA levels were compared between control and insulin-treated mouse liver tissues cultured ex vivo and immortalized mouse hepatocytes AML12. To determine the role of Fto in the regulation of gluconeogenic gene expression, we examined the effect of enhanced Fto expression on G6pase and Pepck mRNA levels in AML12 cells. Key findings Fto mRNA levels were significantly reduced in hyperglycemic/hyperinsulinemic mice compared to normoglycemic/normoinsulinemic mice, while they were indistinguishable between hyperglycemic/hypoinsulinemic mice and normoglycemic/normoinsulinemic mice. Insulin treatment reduced Fto , G6pase , and Pepck mRNA levels compared to control vehicle treatment in both ex vivo cultured mouse liver tissues and AML12 cells. Enhanced Fto expression significantly increased G6pase and Pepck mRNA level in AML12 cells. Significance Our findings support the hypothesis that hepatic Fto participates in the maintenance of glucose homeostasis possibly by mediating the inhibitory effect of glucose and insulin on gluconeogenic gene expression in liver. It is further suggested that impairments in nutritional and hormonal regulation of hepatic Fto expression may lead to impairments in glycemic control in diabetes.

Coal gasification is a key technology for converting coal into substitute natural gas (SNG), the common feedstock for synthesis of chemicals and electricity generation. Now, the development of coal gasification technologies is conducted for commercialization all over the world. Nippon Steel & Sumikin Engineering Co., Ltd. developed the innovative coal gasification technology using the highly efficient two-stage entrained flow gasifier (ECOPRO®), and testing has been completed at the pilot plant with a throughput of 20 t/d, verifying applicability of the process to low-rank coals including brown coal as well as its operating stability. This paper reports on the experiences in the development of ECOPRO® and results from operating the pilot plant using brown coal and other low-rank coals as feedstock.