Circulating AIM prevents hepatocellular carcinoma through complement activation.

Hepatocellular carcinoma (HCC) is a widespread fatal disease and the third most common cause of cancer deaths. Here, we show the potent anti-HCC effect of the circulating protein AIM. As in adipocytes, AIM is incorporated into normal hepatocytes, where it interferes with lipid storage. In contrast, AIM accumulates on the HCC cell surface and activates the complement cascade via inactivating multiple regulators of complement activation. This response provokes necrotic cell death specifically in AIM-bound HCC cells. Accordingly, AIM(-/-) mice were highly susceptible to steatosis-associated HCC development, whereas no AIM(+/+) mouse developed the disease despite comparable liver inflammation and fibrosis in response to a long-term high-fat diet. Administration of AIM prevented tumor development in AIM(-/-) mice, and HCC induction by diethylnitrosamine was more prominent in AIM(-/-) than wild-type mice. These findings could be the basis for novel AIM-based therapeutic strategies for HCC.

Verification of NOx emission inventories over North Korea.

In this study, the top-down NOx emissions estimated from satellite observations of NO2 vertical column densities over North Korea from 1996 to 2009 were analyzed. Also, a bottom-up NOx emission inventory from REAS 1.1 from 1980 to 2005 was analyzed with several statistics. REAS 1.1 was in good agreement with the top-down approach for both trend and amount. The characteristics of NOx emissions in North Korea were quite different from other developed countries including South Korea. In North Korea, emissions from industry sector was the highest followed by transportation sector in the 1980s. However, after 1990, the NOx emissions from other sector, mainly agriculture, became the 2nd highest. Also, no emission centers such as urban areas or industrial areas were distinctively observed. Finally, the monthly NOx emissions were high during the warm season.

Influence of model grid resolution on NO2 vertical column densities over East Asia.

UNLABELLED: NO2 vertical column densities (VCDs) over East Asia in June and December 2007 were simulated by the Community Multi-scale Air Quality (CMAQ) version 4.7.1 using an updated and more elaborate version of the Regional Emission Inventory in Asia (REAS) version 2. The modeling system could reasonably capture observed spatiotemporal changes of NO2 VCDs by satellite sensors, the Global Ozone Monitoring Experiment-2 (GOME-2), the Scanning Imaging Absorption Spectrometer for Atmospheric Cartography (SCIAMACHY), and the Ozone Monitoring Instrument (OMI), even at the coarsest horizontal resolution of 80 km. The CMAQ simulations were performed in a sequence of three horizontal resolutions (80 km, 40 km, and 20 km) for June and December 2007 to investigate the influence of changes of horizontal resolution on the obtained NO2 VCDs. CMAQ-simulated NO2 VCDs generally increased with improvements in resolution from 80 km to 40 km and then to 20 km. Increases in the CMAQ-simulated NO2 VCDs were greater for the change from 80 km to 40 km than for those from 40 km and 20 km, in which the increases of NO2 VCDs due to the improvement of horizontal resolution were approached convergence at the horizontal resolution of approximately 20 km. Conversely, no clear convergences in NO2 VCDs changes were found at near Tokyo and over the East China Sea. The biases of the NO2 VCDs simulated at a resolution of 20 km against the satellite retrievals were -36% near Beijing (CHN1) and -78% near Shanghai (CHN2) in summer; these errors were found to be comparable to the horizontal resolution-dependent errors, which were 18-25% at CHN1 and 44-58% at CHN2 from 80 km to 40 km. Conversely, the influence of changes of horizontal resolution in winter was relatively less compared to that in summer. IMPLICATIONS: NO2 VCDs over East Asia in June and December 2007 were simulated using CMAQ version 4.7.1 and REAS version 2. The modeling system could reasonably capture observed spatiotemporal changes of NO2 VCDs by satellite sensors. The CMAQ simulations were performed in a sequence of three horizontal resolutions, 80, 40, and 20 km, to investigate the influence of changes of horizontal resolution on the obtained NO2 VCDs. The results suggested that the influence of changes of horizontal resolution was larger in summer compared to that in winter. The magnitude of the influence was comparable to the biases of the NO2 VCDs simulated at a resolution of 20 km against the satellite retrievals.

Sensitivity analysis of source regions to PM2.5 concentration at Fukue Island, Japan.

UNLABELLED: The authors analyze the sensitivities of source regions in East Asia to PM2.5 (particulate matter with an aerodynamic diameter of < or = 2.5 microm) concentration at Fukue Island located in the western part of Japan by using a regional chemical transport model with emission sensitivity simulations for the year 2010. The temporal variations in PM2.5 concentration are generally reproduced, but the absolute concentration is underestimated by the model. Chemical composition of PM2.5 in the model is compared with filter sampling data in spring; simulated sulfate, ammonium, and elemental carbon are consistent with observations, but mass concentration of particulate organic matters is underestimated. The relative contribution from each source region shows the seasonal variation, especially in summer. The contribution from central north China (105 degrees E-124 degrees E, 34 degrees N-42 degrees N) accounts for 50-60% of PM2.5 at Fukue Island except in summer; it significantly decreases in summer (18%). Central south China (105 degrees E-123 degrees E, 26 degrees N-34 degrees N) has the relative contribution of 15-30%. The contribution from the Korean Peninsula is estimated at about 10% except in summer. The domestic contribution accounts for about 7% in spring and autumn and increases to 19% in summer. We also estimate the relative contribution to daily average concentration in high PM2.5 days (> 35 microg m(-3)). Central north China has a significant contribution of 60-70% except in summer. The relative contribution from central south China is estimated at 46% in summer and about 30% in the other seasons. The contributions from central north and south China on high PM2.5 days are generally larger than those of their seasonal mean contributions. The domestic contribution is smaller than the seasonal mean value in every season; it is less than 10% even in summer. These model results suggest that foreign anthropogenic sources have a substantial impact on attainment of the atmospheric environmental standard of Japan at Fukue Island. IMPLICATIONS: The contribution from several source regions in East Asia to PM2.5 concentration at Fukue Island, a remote island located in the western part of Japan and close to the Asian continent, is estimated using a three-dimensional chemical transport model. The model results suggest that PM2.5 that is attributed to foreign anthropogenic sources have a larger contribution than that of domestic pollution and have a substantial impact on attainment of the atmospheric environmental standard of Japan at Fukue Island.

Source contribution analysis of surface particulate polycyclic aromatic hydrocarbon concentrations in northeastern Asia by source-receptor relationships.

We analyzed the source-receptor relationships for particulate polycyclic aromatic hydrocarbon (PAH) concentrations in northeastern Asia using an aerosol chemical transport model. The model successfully simulated the observed concentrations. In Beijing (China) benzo[a]pyren (BaP) concentrations are due to emissions from its own domain. In Noto, Oki and Tsushima (Japan), transboundary transport from northern China (>40 °N, 40-60%) and central China (30-40 °N, 10-40%) largely influences BaP concentrations from winter to spring, whereas the relative contribution from central China is dominant (90%) in Hedo. In the summer, the contribution from Japanese domestic sources increases (40-80%) at the 4 sites. Contributions from Japan and Russia are additional source of BaP over the northwestern Pacific Ocean in summer. The contribution rates for the concentrations from each domain are different among PAH species depending on their particulate phase oxidation rates. Reaction with O3 on particulate surfaces may be an important component of the PAH oxidation processes.

Obesity-associated autoantibody production requires AIM to retain the immunoglobulin M immune complex on follicular dendritic cells.

Natural immunoglobulin M (IgM) is reactive to autoantigens and is believed to be important for autoimmunity. Blood pentameric IgM loaded with antigens forms a large immune complex (IC) that contains various elements, including apoptosis inhibitor of macrophage (AIM). Here we demonstrate that this IgM-AIM association contributes to autoantibody production under obese conditions. In mice fed a high-fat diet, natural IgM increased through B cell TLR4 stimulation. AIM associated with IgM and protected AIM from renal excretion, increasing blood AIM levels along with the obesity-induced IgM augmentation. Meanwhile, the AIM association inhibited IgM binding to the Fcα/µ receptor on splenic follicular dendritic cells, thereby protecting the IgM IC from Fcα/µ receptor-mediated internalization. This supported IgM-dependent autoantigen presentation to B cells, stimulating IgG autoantibody production. Accordingly, in obese AIM-deficient (AIM(-/-)) mice, the increase of multiple IgG autoantibodies observed in obese wild-type mice was abrogated. Thus, the AIM-IgM association plays a critical role in the obesity-associated autoimmune process.

Emission and atmospheric transport of particulate PAHs in Northeast Asia.

The emission, concentration levels, and transboundary transport of particulate polycyclic aromatic hydrocarbons (PAHs) in Northeast Asia were investigated using particulate PAH measurements, the newly developed emission inventory (Regional Emission inventory in ASia for Persistent Organic Pollutants version, REAS-POP), and the chemical transport model (Regional Air Quality Model ver2 for POPs version, RAQM2-POP). The simulated concentrations of the nine particulate PAHs agreed well with the measured concentrations, and the results firmly established the efficacy of REAS/RAQM2-POP. It was found that the PAH concentrations in Beijing (China, source region), which were emitted predominantly from domestic coal, domestic biofuel, and other transformations of coal (including coke production), were approximately 2 orders of magnitude greater than those monitored at Noto (Japan, leeward region). In Noto, the PAH concentrations showed seasonal variations; the PAH concentrations were high from winter to spring due to contributions from domestic coal, domestic biofuel, and other transformations of coal, and low in summer. In summer, these contribution were decrease, instead, other sources, such as the on-road mobile source, were relatively increased compared with those in winter. These seasonal variations were due to seasonal variations in emissions from China, as well as transboundary transport across the Asian continent associated with meteorological conditions.

AIMing at metabolic syndrome. -Towards the development of novel therapies for metabolic diseases via apoptosis inhibitor of macrophage (AIM).-.

Metabolic syndrome (MetS) is a cascade of metabolic diseases, starting with obesity and progressing to atherosclerosis, and is often fatal because of serious cardiovascular problems such as heart/brain infarction and hemorrhage. Accumulating evidence has revealed a critical involvement of inflammatory responses triggered by lesional macrophages in the pathogenesis of MetS. Importantly, we found that macrophages are associated with disease progression, not only in the induction of inflammation but also in the production of apoptosis inhibitor of macrophages (AIM), which we initially identified as a soluble factor expressed by macrophages. In atherosclerotic plaques, AIM is highly expressed by foam macrophages and inhibits apoptosis of these cells, which results in the accumulation of macrophages, causing inflammatory responses within the lesion, and ultimately disease progression. In adipose tissue, macrophage-derived AIM is incorporated into adipocytes through CD36-mediated endocytosis, thereby reducing the activity of cytosolic fatty acid synthase. This unique response stimulates lipolysis, resulting in a decrease in adipocyte size, which is physiologically relevant to the prevention of obesity. The lipolytic response also stimulates inflammation of adipocytes in association with the induction of metabolic disorders subsequent to obesity. Thus, AIM is involved in the progression of MetS in both an advancing and inhibitory fashion. Regulation of AIM could therefore be therapeutically applicable for MetS.

Apoptosis inhibitor of macrophage (AIM) is required for obesity-associated recruitment of inflammatory macrophages into adipose tissue.

Infiltration of inflammatory macrophages into adipose tissues with the progression of obesity triggers insulin resistance and obesity-related metabolic diseases. We recently reported that macrophage-derived apoptosis inhibitor of macrophage (AIM) protein is increased in blood in line with obesity progression and is incorporated into adipocytes, thereby inducing lipolysis in adipose tissue. Here we show that such a response is required for the recruitment of adipose tissue macrophages. In vitro, AIM-dependent lipolysis induced an efflux of palmitic and stearic acids from 3T3-L1 adipocytes, thereby stimulating chemokine production in adipocytes via activation of toll-like receptor 4 (TLR4). In vivo administration of recombinant AIM to TLR4-deficient (TLR4(-/-)) mice resulted in induction of lipolysis without chemokine production in adipose tissues. Consistently, mRNA levels for the chemokines that affect macrophages were far lower in AIM-deficient (AIM(-/-)) than in wild-type (AIM(+/+)) obese adipose tissue. This reduction in chemokine production resulted in a marked prevention of inflammatory macrophage infiltration into adipose tissue in obese AIM(-/-) mice, although these mice showed more advanced obesity than AIM(+/+) mice on a high-fat diet. Diminished macrophage infiltration resulted in decreased inflammation locally and systemically in obese AIM(-/-) mice, thereby protecting them from insulin resistance and glucose intolerance. These results indicate that the increase in blood AIM is a critical event for the initiation of macrophage recruitment into adipose tissue, which is followed by insulin resistance. Thus, AIM suppression might be therapeutically applicable for the prevention of obesity-related metabolic disorders.

Death effector domain-containing protein (DEDD) is required for uterine decidualization during early pregnancy in mice.

During intrauterine life, the mammalian embryo survives via its physical connection to the mother. The uterine decidua, which differentiates from stromal cells after implantation in a process known as decidualization, plays essential roles in supporting embryonic growth before establishment of the placenta. Here we show that female mice lacking death effector domain-containing protein (DEDD) are infertile owing to unsuccessful decidualization. In uteri of Dedd-/- mice, development of the decidual zone and the surrounding edema after embryonic implantation was defective. This was subsequently accompanied by disintegration of implantation site structure, leading to embryonic death before placentation. Polyploidization, a hallmark of mature decidual cells, was attenuated in DEDD-deficient cells during decidualization. Such inefficient decidualization appeared to be caused by decreased Akt levels, since polyploidization was restored in DEDD-deficient decidual cells by overexpression of Akt. In addition, we showed that DEDD associates with and stabilizes cyclin D3, an important element in polyploidization, and that overexpression of cyclin D3 in DEDD-deficient cells improved polyploidization. These results indicate that DEDD is indispensable for the establishment of an adequate uterine environment to support early pregnancy in mice.

Macrophage-derived AIM is endocytosed into adipocytes and decreases lipid droplets via inhibition of fatty acid synthase activity.

Macrophages infiltrate adipose tissue in obesity and are involved in the induction of inflammation, thereby contributing to the development of obesity-associated metabolic disorders. Here, we show that the macrophage-derived soluble protein AIM is endocytosed into adipocytes via CD36. Within adipocytes, AIM associates with cytosolic fatty acid synthase (FAS), thereby decreasing FAS activity. This decreases lipid droplet size, stimulating the efflux of free fatty acids and glycerol from adipocytes. As an additional consequence of FAS inhibition, AIM prevents preadipocyte maturation. In vivo, the increase in adipocyte size and fat weight induced by high-fat diet (HFD) was accelerated in AIM-deficient (AIM(-)(/-)) mice compared to AIM(+/+) mice. Moreover, injection of recombinant AIM in AIM(-)(/-) mice suppresses the increase in fat mass induced by HFD. Interestingly, metabolic rates are comparable in AIM(-)(/-) and AIM(+/+) mice, suggesting that AIM specifically influences adipocyte status. Thus, this AIM function in adipocytes may be physiologically relevant to obesity progression.

The death effector domain-containing DEDD forms a complex with Akt and Hsp90, and supports their stability.

Insulin secretion and glucose transport are the major mechanisms to balance glucose homeostasis. Recently, we found that the death effector domain-containing DEDD inhibits cyclin-dependent kinase-1 (Cdk1) function, thereby preventing Cdk1-dependent inhibitory phosphorylation of S6 kinase-1 (S6K1), downstream of phosphatidylinositol 3-kinase (PI3K), which overall results in maintenance of S6K1 activity. Here we newly show that DEDD forms a complex with Akt and heat-shock protein 90 (Hsp90), and supports the stability of both proteins. Hence, in DEDD(-/-) mice, Akt protein levels are diminished in skeletal muscles and adipose tissues, which interferes with the translocation of glucose-transporter 4 (GLUT4) upon insulin stimulation, leading to inefficient incorporation of glucose in these organs. Interestingly, as for the activation of S6K1, suppression of Cdk1 is involved in the stabilization of Akt protein by DEDD, since diminishment of Cdk1 in DEDD(-/-) cells via siRNA expression or treatment with a Cdk1-inhibitor, increases both Akt and Hsp90 protein levels. Such multifaceted involvement of DEDD in glucose homeostasis by supporting both insulin secretion (via maintenance of S6K1 activity) and glucose uptake (via stabilizing Akt protein), may suggest an association of DEDD-deficiency with the pathogenesis of type 2 diabetes mellitus.

The death effector domain-containing DEDD supports S6K1 activity via preventing Cdk1-dependent inhibitory phosphorylation.

Cell cycle regulation and biochemical responses upon nutrients and growth factors are the major regulatory mechanisms for cell sizing in mammals. Recently, we identified that the death effector domain-containing DEDD impedes mitotic progression by inhibiting Cdk1 (cyclin-dependent kinase 1) and thus maintains an increase of cell size during the mitotic phase. Here we found that DEDD also associates with S6 kinase 1 (S6K1), downstream of phosphatidylinositol 3-kinase, and supports its activity by preventing inhibitory phosphorylation of S6K1 brought about by Cdk1 during the mitotic phase. DEDD(-/-) cells showed reduced S6K1 activity, consistently demonstrating decreased levels in activating phosphorylation at the Thr-389 site. In addition, levels of Cdk1-dependent inhibitory phosphorylation at the C terminus of S6K1 were enhanced in DEDD(-/-) cells and tissues. Consequently, as in S6K1(-/-) mice, the insulin mass within pancreatic islets was reduced in DEDD(-/-) mice, resulting in glucose intolerance. These findings suggest a novel cell sizing mechanism achieved by DEDD through the maintenance of S6K1 activity prior to cell division. Our results also suggest that DEDD may harbor important roles in glucose homeostasis and that its deficiency might be involved in the pathogenesis of type 2 diabetes mellitus.

Algorithm improvement and validation of National Institute for Environmental Studies ozone differential absorption lidar at the Tsukuba Network for Detection of Stratospheric Change complementary station.

Recently, a data processing and retrieval algorithm (version 2) for ozone, aerosol, and temperature lidar measurements was developed for an ozone lidar system at the National Institute for Environmental Studies (NIES) in Tsukuba (36 degrees N,140 degrees E), Japan. A method for obtaining the aerosol boundary altitude and the aerosol extinction-to-backscatter ratio in the version 2 algorithm enables a more accurate determination of the vertical profiles of aerosols and a more accurate correction of the systematic errors caused by aerosols in the vertical profile of ozone. Improvements in signal processing are incorporated for the correction of systematic errors such as the signal-induced noise and the dead-time effect. The mean vertical ozone profiles of the NIES ozone lidar were compared with those of the Stratospheric Aerosol and Gas Experiment II (SAGE II); they agreed well within a 5% relative difference in the 20-40 km altitude range and within 10% up to 45 km. The long-term variations in the NIES ozone lidar also showed good coincidence with the ozonesonde and SAGE II at 20, 25, 30, and 35 km. The temperatures retrieved from the NIES ozone lidar and those given by the National Center for Environmental Prediction agreed within 7 K in the 35-50 km range.

[A case of osteosarcoma in pelvic bone following radiation therapy for prostate cancer].

A case of osteosarcoma in pelvic bone following radiation therapy for prostate cancer is reported. A 74-year-old patient was diagnosed with prostate cancer 10 years ago and started on the endocrine therapy with LH-RH agonist. He had no apparent distant metastasis, and received radiation therapy 8 years ago. He has complained of low back pain since several months ago. A high uptake on bone scintigram and osteolytic and osteoblastic damages on CT were noted in pubic bone and sacrum. The PSA level was less than 0.2 ng/ml. Pathohistological diagnosis by biopsy of the pubic bone was chondroblastic type osteosarcoma, showing an atypical cell proliferation with osteoid. Immunostaining for nonepithelial marker vimentin was positive. He underwent heavy ion radiation therapy for osteosarcoma at the National Institute of Radiological Sciences. Osteosarcoma is one of the rare delayed complications after radiation therapy and requires biopsy for correct diagnosis.