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Summary: Human genetics studies have uncovered genetic variants that can be used to guide biological research and prioritize molecular targets for therapeutic intervention for complex diseases. We have identified a missense variant (P746S) in EDEM3 associated with lower blood triglyceride (TG) levels in >300,000 individuals. Functional analyses in cell and mouse models show that EDEM3 deficiency strongly increased the uptake of very-low-density lipoprotein and thereby reduced the plasma TG level, as a result of up-regulated expression of LRP1 receptor. We demonstrate that EDEM3 deletion up-regulated the pathways for RNA and endoplasmic reticulum protein processing and transport, and consequently increased the cell surface mannose-containing glycoproteins, including LRP1. Metabolomics analyses reveal a cellular TG accumulation under EDEM3 deficiency, a profile consistent with individuals carrying EDEM3 P746S. Our study identifies EDEM3 as a regulator of blood TG, and targeted inhibition of EDEM3 may provide a complementary approach for lowering elevated blood TG concentrations. : Genetics; Diabetology; Specialized Functions of Cells; Metabolomics Subject Areas: Genetics, Diabetology, Specialized Functions of Cells, Metabolomics

Cymbals are percussion instruments that vibrate and radiate sounds when hit with a stick. A bell is the raised section in the middle of the cymbal and its size produces different sounds. In this study, we investigate the effect of bell size on the sound characteristics of cymbals. The radiated sounds and vibrations for cymbals with two different bell sizes are measured. In addition, the natural frequency and mode shape are obtained by finite element analysis and the sound radiation efficiency is calculated for each mode. The measured results indicate that the sound frequency characteristics for the large bell show three peaks with large sound pressure within the range of 1000 to 3000 Hz and the sound pressure for the small bell is larger than that for the large bell within the range of 4000 to 5000 Hz. The vibration frequency characteristics show there is no remarkable difference between the large and small bells. The sound radiation efficiencies indicate that the large bell has many modes with high radiation efficiency within the range of 1000 to 3000 Hz and their modes have a small number of nodal diameters and a large deformation at the bell. The small bell has many modes with high efficiency within the range of 4000 to 5000 Hz. This is reason for the difference in sound characteristics between the large and small bells.

Abstract Background Previously, we have reported that daily glucose fluctuations could affect coronary plaque vulnerability, but the underlying mechanisms remained unclear. This study sought to investigate the impact of CD14++CD16+ monocytes on plaque vulnerability, as assessed by virtual histology intravascular ultrasound (VH-IVUS), as well as their relationship to fluctuating glucose levels in patients with asymptomatic coronary artery disease (CAD). Methods Fifty-one patients with asymptomatic CAD, who were undergoing lipid-lowering therapy and underwent VH-IVUS evaluation for angiographically mild to moderate lesions, were enrolled in the study. Standard VH-IVUS parameters, including the percentage volume of the necrotic core (%NC) within the plaque and the presence of a virtual histology thin-cap fibroatheroma (VH-TCFA), were then evaluated. Additionally, monocyte subsets were assessed by flow cytometry, and daily glucose fluctuations were analyzed by measuring the mean amplitude of glycemic excursion (MAGE). Results Among 82 plaques from 22 diabetes mellitus (DM) patients and 29 non-DM patients, 15 VH-TCFAs were identified. CD14++CD16+ monocyte counts significantly correlated with both %NC and the presence of VH-TCFA (%NC: r = 0.339, p = 0.002; VH-TCFA: p = 0.003). Multivariate logistic regression analysis revealed that CD14++CD16+ monocyte counts were independently associated with VH-TCFA (odds ratio = 1.029, p = 0.004). Furthermore, CD14++CD16+ monocyte counts were significantly correlated with the MAGE score in the non-DM patients (r = 0.544, p = 0.005). Conclusions CD14++CD16+ monocyte levels are associated with coronary plaque vulnerability and can serve as a biomarker for VH-TCFA in patients with CAD undergoing lipid-lowering therapy. In patients without DM, glucose fluctuations may alter the balance of monocyte subsets. Trial registration UMIN Registry number: UMIN000021228

The gut microbiota were shown to play critical roles in the development of atherosclerosis, but the detailed mechanism is limited. The purpose of this study is to clarify the influence of gut microbiota on atherogenesis via lipid metabolism and systemic inflammation. Germ-free or conventionally raised (Conv) ApoE-deficient (ApoE−/−) mice were fed chow diet and euthanized at 20 weeks of age. We found that the lack of gut microbiota in ApoE−/− mice caused a significant increase in the plasma and hepatic cholesterol levels compared with Conv ApoE−/− mice. The absence of gut microbiota changed the bile acid composition in the ileum, which was associated with activation of the enterohepatic fibroblast growth factor 15, fibroblast growth factor receptor 4 axis, and reduction of cholesterol 7α-hydroxylase and hepatic bile acid synthesis, resulting in the accumulation of liver cholesterol content. However, we found that the lack of microbiota caused a significant reduction in atherosclerotic lesion formation compared with Conv ApoE−/− mice, which might be associated with the attenuation of lipopolysaccharide-mediated inflammatory responses. Our findings indicated that the gut microbiota affected both hypercholesterolemia and atherogenesis in mice.

OBJECTIVE:: Obesity in rodents and humans is mostly associated with elevated plasma leptin concentrations, suggesting a new pathological concept of 'leptin resistance'. We have demonstrated that brain-derived neurotrophic factor (BDNF) can improve obesity and diabetes of C57BL/KsJ db/db (db/db) mice. In this study, we investigated whether or not BDNF is effective in two different models of leptin resistance, an acquired model and a genetic model. DESIGN:: C57BL/6J mice rendered obese by consumption of a high-fat diet (diet-induced obesity (DIO) mice) were used as an acquired model and lethal yellow agouti mice (KKAy mice) as a genetic model of leptin resistance. Food intake and glucose metabolism were studied after acute or repetitive administration of BDNF. RESULTS:: Intraperitoneal administration of BDNF (10?mg/kg, twice/day) significantly reduced cumulative food intake of DIO and KKAy mice, whereas they were unresponsive to leptin administration. Repetitive subcutaneous administration of BDNF (10?mg/kg daily for 6 days) reduced food intake and improved impaired glucose tolerance in DIO mice. Pair feeding of vehicle-treated DIO mice with the same amount of chow consumed by the BDNF-treated group did not improve the impaired glucose homeostasis, indicating that the antidiabetic effect is not due to decreased food intake. We also observed that BDNF is effective in improving obesity and diabetes of KKAy mice. CONCLUSION:: This study demonstrated antiobesity and antidiabetic effects of BDNF in two different models of leptin resistance, thereby suggesting the therapeutic potential of BDNF in the treatment of leptin-resistant obesity and diabetes.International Journal of Obesity (2003) 27, 557-565. doi:10.1038/sj.ijo.0802265 [ABSTRACT FROM AUTHOR]

Only a few patients have been reported to undergo endovascular therapy for Trousseau syndrome. This is the first report of a patient with Trousseau syndrome who developed synchronous cardiocerebral infarction and underwent endovascular therapy for both. A 55-year-old woman with Trousseau syndrome arising from stage IV ovarian cancer presented with consciousness disturbance, aphasia, and right hemiparesis. Magnetic resonance imaging showed acute cerebral infarction limited to the left basal ganglia and occlusion of the left middle cerebral artery (MCA). Electrocardiography showed ST elevation in leads II, III, and aVF with reciprocal change. Mild elevation of myocardial enzymes was observed in laboratory data. She was diagnosed with synchronous cardiocerebral infarction. Both infarctions were considered as appropriately indicated for endovascular therapy. Since her vital signs were stable, a decision was made to treat the cerebral infarction first. Thrombectomy with a stent retriever was performed, which achieved complete recanalization of the left MCA. Percutaneous coronary intervention successfully recanalized the occluded right coronary artery. She suffered no recurrence of stroke or acute coronary syndrome upon heparin administration. Cardiocerebral infarction caused by Trousseau syndrome is rare and demands optimal planning of endovascular therapy.

Hypoparathyroidism and osteoporosis can be treated with parathyroid hormone, but frequent injections are required. Here the authors develop a small-molecule agonist for the parathyroid hormone type I receptor that can be administered orally, and demonstrate its efficacy in rats.

BackgroundPathogenic immune responses are known to play an important role in abdominal aortic aneurysm (AAA) development. Ultraviolet B (UVB) irradiation has been demonstrated to have therapeutic potential not only for cutaneous diseases but also for systemic inflammatory diseases in mice by suppressing immunoinflammatory responses. We investigated the effect of UVB irradiation on experimental AAA. Methods and ResultsWe used an angiotensin II–induced AAA model in apolipoprotein E–deficient mice fed a high‐cholesterol diet. Mice aged 10 weeks were irradiated with 5 kJ/m2 UVB once weekly for 6 weeks (UVB‐irradiated, n=38; nonirradiated, n=42) and were euthanized for evaluation of AAA formation at 16 weeks. Overall, 93% of angiotensin II–infused mice developed AAA, with 60% mortality possibly because of aneurysm rupture. UVB irradiation significantly decreased the incidence (66%) and mortality (29%) of AAA (P=0.004 and P=0.006, respectively). UVB‐irradiated mice had significantly smaller diameter AAA (P=0.008) and fewer inflammatory cells in the aortic aneurysm tissue than nonirradiated mice, along with systemic expansion of CD4+Foxp3+ regulatory T cells and decreased effector CD4+CD44highCD62Llow T cells in para‐aortic lymph nodes. Genetic depletion of regulatory T cells abrogated these beneficial effects of UVB treatment, demonstrating a critical role of regulatory T cells. ConclusionsOur data suggest that UVB‐dependent expansion of regulatory T cells has beneficial effects on experimental AAA and may provide a novel strategy for the treatment of AAA.

Cymbals are percussion instruments that vibrate and radiate sounds when hit with a stick or when used in pairs. The sound radiated from a cymbal depends on its vibration characteristics. Cymbals are made through spin forming, hammering and lathing processes. The spin forming creates the domed shape of cymbals, determining the basic vibration characteristics. The hammering and lathing make specific sound quality adjustments by changing the vibration characteristics. In this paper, we focus on how the hammering affects the cymbal's vibration characteristics. The hammering produces many shallow dents over the cymbal's surface, generating residual stresses in it. These residual stresses change the vibration characteristics. We perform finite element analysis of the hammered cymbal to obtain its vibration characteristics. In the analysis, we use thermal stress analysis to reproduce the stress distribution and then with this stress distribution we perform vibration analysis. The results show that the effects of thermal load (i.e., hammering) vary depending on the mode: an increase or decrease in the natural frequency. As a result, the peak frequencies and their peak values in the frequency response function change.

This report describes the result of meteorological observations at Syowa Station by the Meteorological Observation Team of the 49th Japanese Antarctic Research Expedition (JARE-49) during the period 1 February 2008 to 27 January 2009. The observation methods, instruments, and statistical methods used by the JARE-49 team are nearly the same as those used by the JARE-48 observation team. Remarkable weather phenomena observed during the period of JARE-49 are as follows. 1) On 1 September 2008, the record minimum temperature for September was observed in the upper atmosphere (pressure greater than 175 hPa). 2) The monthly mean temperature at Syowa Station during October 2008 was -17.5°C; this is the lowest monthly mean October temperature recorded at Syowa Station. 3) The total ozone over Syowa Station was less than or equal to 220 m atm-cm during the period from late August to late November, and was close to minimum levels during the period from mid-September to mid-October. The lowest total ozone in 2008, recorded on 16 October 2008, was 140 m atm-cm.

Nephrin is a critical component of glomerular filtration barrier, which is important to maintain glomerular structure and avoid proteinuria. Downregulation of nephrin expression is commonly observed at early stage of glomerular disorders, suggesting that methods to increase nephrin expression in podocytes may have therapeutic utility. Here, we generated a knockin mouse line carrying single copy of 5.5 kb nephrin promoter controlling expression of enhanced green fluorescent protein (EGFP) at Rosa26 genomic locus (Nephrin-EGFP mouse). In these mice, EGFP was specifically expressed in podocytes. Next, we isolated and cultivated glomeruli from these mice, and developed a protocol to automatically quantitate EGFP expression in cultured glomeruli. EGFP signal was markedly reduced after 5 days of culture but reduction was inhibited by vitamin D treatment. We confirmed that vitamin D increased mRNA and protein expression of endogenous nephrin in cultivated glomeruli. Thus, we generated a mouse line converting nephrin promoter activity into fluorescence, which can be used to screen compounds having activity to enhance nephrin gene expression.

Fibrosis is a final common pathway leading to loss of kidney function, in which the fibrogenic cytokine, transforming growth factor β (TGF-β), plays a central role. While previous studies showed that TGF-β antagonism by various means prevents fibrosis in mouse models, clinical approaches based on these findings remain elusive. 1D11 is a neutralizing antibody to all three isoforms of TGF-β. In both adriamycin (ADR)-induced nephropathy and NEP25 podocyte ablation nephropathy, thrice-weekly intraperitoneal administration of 1D11 from the day of disease induction until the mice were sacrificed (day 14 for ADR and day 28 for NEP25), significantly reduced glomerular COL1A2 mRNA accumulation and histological changes. Consistent with our previous findings, proteinuria remained overt in the mice treated with 1D11, suggesting distinct mechanisms for proteinuria and fibrogenesis. Podocyte numbers determined by WT1 staining were significantly reduced in NEP25-model glomeruli as expected, while WT1-positive cells were preserved in mice receiving 1D11. Even when 1D11 was administered after the onset of proteinuria on day 3, 1D11 preserved WT1-positive cell numbers in glomeruli and significantly reduced glomerular scar score (2.5 ± 0.2 [control IgG] vs. 1.8 ± 0.2 [1D11], P < 0.05) and glomerular COL1A2 mRNA expression (19.3 ± 4.4 [control IgG] vs. 8.4 ± 2.4 [1D11] fold increase over the healthy control, P < 0.05). Transmission electron microscopy revealed loss of podocytes and denuded glomerular basement membrane in NEP25 mice with disease, whereas podocytes remained attached to the basement membrane, though effaced and swollen, in those receiving 1D11 from day 3. Together, these data suggest that TGF-β neutralization by 1D11 prevents glomerular fibrosis even when started after the onset of proteinuria. While overt proteinuria and podocyte effacement persist, 1D11 prevents total podocytes detachment, which might be a key event activating fibrogenic events in glomeruli.

As a part of summer observations of the 49th Japanese Antarctic Research Expedition, stratospheric whole air sampling experiments were conducted at Syowa Station using newly developed compact cryogenic air samplers. The compact sampler uses liquefied neon (produced in-situ) as a refrigerant to solidify or liquefy atmospheric constituents. Because of its reduced size and weight, the sampler can be launched using small-size balloons (1000–2000 m3 in volume). On December 30, 2007 and January 4, 2008, a total of 4 samplers were launched from Syowa Station and recovered on the same day as their launches. Two of them functioned as designed and collected stratospheric air samples at altitudes of 18 and 25 km. The air samples were analyzed for greenhouse gas concentrations and stable isotopes after return to Japan.

The renin-angiotensin system (RAS) plays a central role in blood pressure regulation. Although clinical and experimental studies have suggested that inhibition of RAS is associated with progression of anemia, little evidence is available to support this claim. Here we report that knockout mice that lack angiotensin II, including angiotensinogen and renin knockout mice, exhibit anemia. The anemia of angiotensinogen knockout mice was rescued by angiotensin II infusion, and rescue was completely blocked by simultaneous administration of AT1 receptor blocker. To genetically determine the responsible receptor subtype, we examined AT1a, AT1b, and AT2 knockout mice, but did not observe anemia in any of them. To investigate whether pharmacological AT1 receptor inhibition recapitulates the anemic phenotype, we administered AT1 receptor antagonist in hypotensive AT1a receptor knockout mice to inhibit the remaining AT1b receptor. In these animals, hematocrit levels barely decreased, but blood pressure further decreased to the level observed in angiotensinogen knockout mice. We then generated AT1a and AT1b double-knockout mice to completely ablate the AT1 receptors; the mice finally exhibited the anemic phenotype. These results provide clear evidence that although erythropoiesis and blood pressure are negatively controlled through the AT1 receptor inhibition in vivo, the pathways involved are complex and distinct, because erythropoiesis is more resistant to AT1 receptor inhibition than blood pressure control.

Blood filtration in the kidney glomerulus is essential for physiological homeostasis. The filtration apparatus of the kidney glomerulus is composed of three distinct components: the fenestrated endothelial cells, the glomerular basement membrane, and interdigitating foot processes of podocytes that form the slit diaphragm. Recent studies have demonstrated that podocytes play a crucial role in blood filtration and in the pathogenesis of proteinuria and glomerular sclerosis; however, the molecular mechanisms that organize the podocyte filtration barrier are not fully understood. In this study, we suggest that tight junction protein 1 (Tjp1 or ZO-1), which is encoded by Tjp1 gene, plays an essential role in establishing the podocyte filtration barrier. The podocyte-specific deletion of Tjp1 down-regulated the expression of podocyte membrane proteins, impaired the interdigitation of the foot processes and the formation of the slit diaphragm, resulting in glomerular dysfunction. We found the possibility that podocyte filtration barrier requires the integration of two independent units, the pre-existing epithelial junction components and the newly synthesized podocyte-specific components, at the final stage in glomerular morphogenesis, for which Tjp1 is indispensable. Together with previous findings that Tjp1 expression was decreased in glomerular diseases in human and animal models, our results indicate that the suppression of Tjp1 could directly aggravate glomerular disorders, highlights Tjp1 as a potential therapeutic target.

Podocyte injury is the first step in the progression of glomerulosclerosis. Previous studies have demonstrated the beneficial effect of bone morphogenetic protein 7 (Bmp7) in podocyte injury and the existence of native Bmp signaling in podocytes. Local activity of Bmp7 is controlled by cell-type specific Bmp antagonists, which inhibit the binding of Bmp7 to its receptors. Here we show that the product of Twisted gastrulation (Twsg1), a Bmp antagonist, is the central negative regulator of Bmp function in podocytes and that Twsg1 null mice are resistant to podocyte injury. Twsg1 was the most abundant Bmp antagonist in murine cultured podocytes. The administration of Bmp induced podocyte differentiation through Smad signaling, whereas the simultaneous administration of Twsg1 antagonized the effect. The administration of Bmp also inhibited podocyte proliferation, whereas simultaneous administration of Twsg1 antagonized the effect. Twsg1 was expressed in the glomerular parietal cells (PECs) and distal nephron of the healthy kidney, and additionally in damaged glomerular cells in a murine model of podocyte injury. Twsg1 null mice exhibited milder hypoalbuminemia and hyperlipidemia, and milder histological changes while maintaining the expression of podocyte markers during podocyte injury model. Taken together, our results show that Twsg1 plays a critical role in the modulation of protective action of Bmp7 on podocytes, and that inhibition of Twsg1 is a promising means of development of novel treatment for podocyte injury.

Background. Recently, endoscopic submucosal dissection (ESD) has become a standard treatment method for early gastric cancer and concurrent stomach preservation. However, metachronous recurrences have become a major problem. We evaluated the incidence and clinicopathologic features of and examined the risk factors for metachronous gastric tumors. Methods. A total of 357 patients who underwent ESD for gastric tumors (245 early gastric cancers and 112 adenomas) and were followed up for more than 12 months without recurrence within the first 12 months were enrolled. We investigated the incidence and clinicopathologic features of metachronous tumors after ESD. We also analyzed the potential risk factors for metachronous tumors using the Kaplan-Meier method and Cox’s proportional hazards model. Results. The annual incidence of metachronous tumors after ESD was 2.4%. The median period until discovery after initial ESD was 26.0 months, and the median observation period was 52.6 months. Male patients developed metachronous tumors more frequently (P=0.04), and the hazard ratio of female to male patients was 0.36 (95% confidence interval: 0.11–0.89). Conclusions. Patients with a previous history of gastric tumors have a high risk of subsequent gastric tumor development and male patients should be carefully followed up after ESD for gastric tumor.