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Aims/hypothesis Non-alcoholic fatty liver disease (NAFLD) associated with type 2 diabetes may more easily progress towards severe forms of non-alcoholic steatohepatitis (NASH) and cirrhosis. Although the Wnt effector transcription factor 7-like 2 (TCF7L2) is closely associated with type 2 diabetes risk, the role of TCF7L2 in NAFLD development remains unclear. Here, we investigated how changes in TCF7L2 expression in the liver affects hepatic lipid metabolism based on the major risk factors of NAFLD development. Methods Tcf7l2 was selectively ablated in the liver of C57BL/6N mice by inducing the albumin (Alb) promoter to recombine Tcf7l2 alleles floxed at exon 5 (liver-specific Tcf7l2-knockout [KO] mice: Alb-Cre;Tcf7l2f/f). Alb-Cre;Tcf7l2f/f and their wild-type (Tcf7l2f/f) littermates were fed a high-fat diet (HFD) or a high-carbohydrate diet (HCD) for 22 weeks to reproduce NAFLD/NASH. Mice were refed a standard chow diet or an HCD to stimulate de novo lipogenesis (DNL) or fed an HFD to provide exogenous fatty acids. We analysed glucose and insulin sensitivity, metabolic respiration, mRNA expression profiles, hepatic triglyceride (TG), hepatic DNL, selected hepatic metabolites, selected plasma metabolites and liver histology. Results Alb-Cre;Tcf7l2f/f essentially exhibited increased lipogenic genes, but there were no changes in hepatic lipid content in mice fed a normal chow diet. However, following 22 weeks of diet-induced NAFLD/NASH conditions, liver steatosis was exacerbated owing to preferential metabolism of carbohydrate over fat. Indeed, hepatic Tcf7l2 deficiency enhanced liver lipid content in a manner that was dependent on the duration and amount of exposure to carbohydrates, owing to cell-autonomous increases in hepatic DNL. Mechanistically, TCF7L2 regulated the transcriptional activity of Mlxipl (also known as ChREBP) by modulating O-GlcNAcylation and protein content of carbohydrate response element binding protein (ChREBP), and targeted Srebf1 (also called SREBP1) via miRNA (miR)-33-5p in hepatocytes. Eventually, restoring TCF7L2 expression at the physiological level in the liver of Alb-Cre;Tcf7l2f/f mice alleviated liver steatosis without altering body composition under both acute and chronic HCD conditions. Conclusions/interpretation In mice, loss of hepatic Tcf7l2 contributes to liver steatosis by inducing preferential metabolism of carbohydrates via DNL activation. Therefore, TCF7L2 could be a promising regulator of the NAFLD associated with high-carbohydrate diets and diabetes since TCF7L2 deficiency may lead to development of NAFLD by promoting utilisation of excess glucose pools through activating DNL. Data availability RNA-sequencing data have been deposited into the NCBI GEO under the accession number GSE162449 (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE162449). Graphical abstract

Magnetoencephalography (MEG) is a functional neuroimaging technique that noninvasively detects the brain magnetic field from neuronal activations. Conventional MEG measures brain signals using superconducting quantum interference devices (SQUIDs). SQUID-MEG requires a cryogenic environment involving a bulky non-magnetic Dewar flask and the consumption of liquid helium, which restricts the variability of the sensor array and the gap between the cortical sources and sensors. Recently, miniature optically pumped magnetometers (OPMs) have been developed and commercialized. OPMs do not require cryogenic cooling and can be placed within millimeters from the scalp. In the present study, we arranged six OPM sensors on the temporal area to detect auditory-related brain responses in a two-layer magnetically shielded room. We presented the auditory stimuli of 1 kHz pure-tone bursts with 200 ms duration and obtained the M50 and M100 components of auditory-evoked fields. We delivered the periodic stimuli with a 40 Hz repetition rate and observed the gamma-band power changes and inter-trial phase coherence of auditory steady-state responses at 40 Hz. We found that the OPM sensors have a performance comparable to that of conventional SQUID-MEG sensors, and our results suggest the feasibility of using OPM sensors for functional neuroimaging and brain–computer interface applications.

Low molecular weight proteins are promising molecules for rice plants. The objectives of this study were to develop an optimized method for protein extractions and protein chips and to perform practical application for isolation of low molecular weight proteins/peptides as potential biomarkers of three rice cultivars, Ilpumbyeo, Hwaseongbyeo, and Nakdongbyeo, using surface-enhanced laser desorption/ionization (SELDI) time-of-flight (TOF) mass spectrometry (MS). Among five protein extraction methods tested, we found that the trichloroacetic acid (TCA)-acetone method was the most effective for the extraction of low molecular weight proteins/peptides. Four protein chip arrays, including CM10 (weak cation exchanger), Q10 (strong anion exchanger), H50 (reverse phage), and IMAC30 (immobilized metal affinity), were used under low and high stringency conditions at varying pH with two energy absorbing molecules, alpha-Cyano-4-hydroxycinnamic acid (CHCA) and sinapinic acid (SA). Of the 70 proteins isolated by the Q10 array, 20 showed significant differences in expression between the three cultivars (p

This study aimed to determine whether the patterns of diabetic complications differed when patients with type 2 diabetes mellitus (T2DM) were simply classified according to insulin sensitivity and beta-cell function. This observational study included 8861 patients with T2DM who underwent concurrent testing for fasting glucose, fasting insulin, and one or more diabetic complications. We categorized the patients into four groups according to insulin sensitivity and beta-cell function. Compared with the reference group (mild insulin resistance and beta-cell dysfunction), the “severe beta-cell dysfunction” group had lower odds of chronic kidney disease [adjusted odds ratios (aOR) 0.611]. The “severe insulin resistance” group had higher odds of carotid artery plaque presence (aOR 1.238). The “severe insulin resistance and beta-cell dysfunction” group had significantly higher odds of large fiber neuropathy (aOR 1.397, all p

Background In this prospective, multicenter, non-comparative observational study, the effectiveness and safety of the triple single-pill combination (SPC) of olmesartan/amlodipine/hydrochlorothiazide (OM/AML/HCTZ) were evaluated in a real clinical practice setting in Korean patients with essential hypertension. Methods A total of 3752 patients were enrolled and followed for 12 months after administration of OM/AML/HCTZ. Primary endpoint was change from baseline to month 6 in the mean systolic blood pressure (SBP). Secondary endpoints included changes from baseline in the mean SBP at month 3, 9, 12 and the mean diastolic blood pressure (DBP) at month 3, 6, 9, 12; changes in the mean SBP/DBP according to age and underlying risk factors; and blood pressure control rate (%) at different time points. Adherence to and satisfaction with OM/AML/HCTZ treatment among patients and physicians were assessed by medication possession ratio (MPR) and numeric rating scale, respectively, as exploratory endpoints. Safety was evaluated by the incidence and severity of adverse events (AEs) as well as the discontinuation rate due to AEs. Results OM/AML/HCTZ administration led to significant reductions in the mean SBP/DBP by 11.5/6.6, 12.3/7.0, 12.3/7.2, and 12.8/7.4 mmHg from baseline to month 3, 6, 9 and 12, respectively (P Conclusions Treatment with the triple SPC of OM/AML/HCTZ demonstrated significant effectiveness in reducing SBP/DBP and achieving target BP control with high adherence over the 1-year observation period in Korean hypertensive patients and was well-tolerated. Trial registration CRIS, KCT0002196, Registered 3 May 2016.

Targeted therapy using phosphatidylinositol 3-kinase (PI3K) inhibitors is used to treat cancer such as lymphoma. In animal studies, its use raised concern about alteration of glucose metabolism. To date, clinical data are inconclusive; therefore, we investigated the incidence and clinical manifestations of diabetes in cancer patients treated with PI3K inhibitors. In a retrospective review of diabetes-free patients with advanced solid tumors treated with PI3K inhibitor, we performed Cox regression to identify independent predictors for the development of diabetes. Of 38 patients (mean age: 54.5 years, 23.7% female) having a mean duration of follow-up of 238.5 days who initiated PI3K inhibitors, 55.3% developed diabetes during treatment (mean 29.1 days); among these, 28.6% experienced remission of diabetes after discontinuing PI3K inhibitors (mean 72.1 days). Patients with incident diabetes had higher anti-hypertensive medication use, higher HbA1c levels and fasting glucose at baseline, and longer duration of PI3K inhibitor use (P = 0.024, P = 0.005, P = 0.008, and P = 0.023, respectively). Previous steroid use and lower baseline HbA1c level were significantly associated with development of diabetes (HR = 8.41, 95% CI 1.89–37.33; HR = 2.16, 95% CI 1.09–4.25, respectively). Patients whose diabetes remitted after discontinuing PI3K inhibitors were younger (P = 0.035) and had lower fasting glucose levels during PI3K inhibitor treatment (P = 0.001) compared to those non-remitters. Previous steroid use and lower baseline HbA1c level may be important predictors for developing diabetes in patients with advanced solid tumors treated with PI3K inhibitors, warranting close observation and careful intervention.

Microneedles (MNs) are being developed to overcome the limitations of the conventional hypodermic needle, e.g. the injection pain. In this study, we conducted an analysis of clinical pain and bleeding at the site of MN insertion and evaluated the insulin pharmacodynamic profile compared with parameters obtained with a conventional pen needle. MN insertion into the skin of 25 healthy adults or 15 patients with type 2 diabetes (T2D) revealed significantly less pain relative to a conventional hypodermic pen needle, thus reducing pain scores from 2.1±1.9 to 1.3±1.4 (mean±standard deviation [SD]). Besides, no bleeding was observed when the MN was used. In the insulin pharmacodynamic assay, no significant differences were observed in the blood glucose-lowering effect between the pen needle and MN. Based on these results, the MN is expected to be a good substitute for conventional hypodermic pen needles and improve the quality of life of patients by significantly reducing the pain associated with insulin treatment.

Background There is increasing concern regarding cardiovascular risk in individuals with non-alcoholic fatty liver disease. This study was conducted to evaluate whether hepatic steatosis with or without fibrosis is associated with the progression of carotid atherosclerosis in patients with type 2 diabetes. Methods From a longitudinal cohort, we enrolled 1120 patients with type 2 diabetes who underwent repeated carotid artery ultrasonography every 1–2 years. Ultrasonographic findings at baseline and after 6–8 years were compared. Presence of hepatic steatosis was mainly assessed by abdominal ultrasonography; patients with hepatic steatosis were further evaluated for hepatic fibrosis according to fibrosis-4 index. We investigated the association between liver status and atherosclerosis progression. Results Of 1120 patients, 636 (56.8%) were classified as having hepatic steatosis at baseline. After 6–8 years, 431 (38.5%) showed atherosclerosis progression. Hepatic steatosis was significantly associated with atherosclerosis progression (adjusted odds ratio[AOR]: 1.370, 95% CI 1.025–1.832; p p p p Conclusions Hepatic steatosis with fibrosis is independently associated with the progression of carotid atherosclerosis in patients with type 2 diabetes.

Current methods for functional group interconversion have, for the most part, relied on relatively strong driving forces which often require highly reactive reagents to generate irreversibly a desired product in high yield and selectivity. These approaches generally prevent the use of the same catalytic strategy to perform the reverse reaction. Here we describe a catalytic functional group metathesis approach to interconvert, under CO-free conditions, two synthetically important classes of electrophiles that are often employed in the preparation of pharmaceuticals and agrochemicals-aroyl chlorides (ArCOCl) and aryl iodides (ArI). Our reaction design relies on the implementation of a key reversible ligand C-P bond cleavage event, which enables a non-innocent, metathesis-active phosphine ligand to mediate a rapid aryl group transfer between the two different electrophiles. Beyond enabling a practical and safer approach to the interconversion of ArCOCl and ArI, this type of ligand non-innocence provides a blueprint for the development of a broad range of functional group metathesis reactions employing synthetically relevant aryl electrophiles.

Turbulence generator (Called turbulence generating plate or perforated plate) of a swirler in low-swirl combustion plays an important role in generating a stable lifted flame with an isotropic turbulence intensity and forming a uniform flow field. According to the previous experimental studies, the typical porosities of the generator in a low-swirl combustor have been reported between 25 % and 40 %. This study focused to confirm these results in terms of various porosities and hole patterns of a turbulence generator in a lab-scale based low swirl combustor. The pressure drop, the flame shapes, the velocity profiles and the emission performances were experimentally investigated to confirm the flame characteristics of low swirl combustion. The outer diameter(2R c) of the turbulence generator was taken to 2R c = 20 mm, and the porosity and the diameter of the circular hole pattern were varied in ranges of 15 - 35 % and 1.5 - 4.5 mm, respectively. The results show that as the porosity decreases, the occurrence of attached flame is encouraged, the lean flammable limit is extended, the flow rate through the turbulence generator decreases, the swirl intensity increases. The central velocity increases, so that the V-shaped flame changes into a flat flame. Also, the minimum velocity in the central low velocity zone increases and the flame liftoff height increases. As the axial velocity increases and the swirl intensity decreases, the effect of outer recirculation decreases, thereby, the temperature of the outer recirculation zone decreases and the exhaust gas temperature increases. Therefore, the NOx emission slightly increases because the flame temperature is increased due to the reduction of outer recirculation influence. As the hole pattern of the turbulence generator becomes a configuration with having more holes for the same porosity, the stable flame region is widened. Also, the velocity uniformity of the central low velocity zone is improved and the turbulence intensity is decreased. These results confirm that the factors of flame stabilization of low swirl combustor are velocity uniformity and turbulence intensity of the turbulence generator.

We investigated the effect of long-term treatment with lobeglitazone, a novel thiazolidinedione-based activator of peroxisome proliferator-activated receptor gamma, on adipose tissue (AT), focusing on its effects on insulin resistance in obese db/db mice. Seven-week-old male db/db mice were assigned to either a vehicle-treated (n=8) or lobeglitazone-treated (n=8) group. Lobeglitazone (1 mg kg−1 daily) was injected intraperitoneally for 20 weeks. Lobeglitazone treatment for 20 weeks resulted in a remarkably improved glycemic index, including significantly decreased glucose levels, enhanced insulin sensitivity and preserved pancreatic beta cells. Both whole body and subcutaneous AT weight increased in the lobeglitazone-treated group. However, lobeglitazone induced an increase in the number of small adipocyte in both epididymal and subcutaneous AT, with a significant weight decrease in the epididymal AT of db/db mice. Using flow cytometry, the CD11c-positive M1 macrophages and CD206-positive M2 macrophages in the epididymal AT were observed to exhibit a decreased M1-to-M2 ratio in lobeglitazone-treated db/db mice. Furthermore, in the lobeglitazone-treated group, interscapular brown AT was clearly visualized by 18F-fluoro-2-deoxy-D-glucose positron emission tomography combined with computed tomography (18F-FDG-PET/CT) and its mass was significantly greater than that of the vehicle-treated group. In the lobeglitazone-treated group, beige-specific gene expression and the number of mitochondria in white AT were upregulated. Lobeglitazone, with upregulating interferon regulatory factor-4 (a key transcriptional regulator of thermogenesis), promoted the development of brown adipocytes and the differentiation of white adipocytes into beige adipocytes. Long-term lobeglitazone treatment has a beneficial role in remodeling and ameliorating inflammation in white AT and in glycemic control, in relation to insulin sensitivity in obese db/db mice. Moreover, lobeglitazone induced the differentiation of brown and beige adipocytes. Collectively, our data suggest that lobeglitazone treatment provides promising effects on white and brown AT as well as great improvement in glycemic control, as a potent insulin sensitizer.

Sodium glucose co-transporter 2 (SGLT2) inhibitors increase urinary glucose excretion (UGE) by reducing the renal threshold for glucose excretion, which results in decreased serum glucose concentrations in patients with type 2 diabetes mellitus (T2D). However, no study to date has determined whether larger increases in UGE after SGLT2 inhibitor treatment correspond to larger reductions in glycated hemoglobin (HbA1C). We enrolled participants who were newly prescribed an SGLT2 inhibitor (dapagliflozin 10 mg or ipragliflozin 50 mg, once daily) as an add-on therapy. Patients were tested for HbA1C and first morning spot urinary-creatinine and -glucose concentrations immediately prior to administration of the SGLT2 inhibitor and at a 12-week follow-up appointment. We investigated the relationship between increases in morning spot UGE and decreases in HbA1C. A total of 101 participants with T2D were enrolled. The median age and diabetes duration were 61.0 and 12.8 years, respectively, and the median HbA1C was 8.10%. SGLT2 inhibitors significantly lowered the HbA1C level, with a median change from baseline to week 12 of −0.60% (p

Two spotted spider mite, Tetranychus urticae, is a polyphagous pest to a variety of plants and they are hard to be controlled due to occurrence of resistance to acaricides. In this study, biochemical evaluation after ethyl formate (EF) and phosphine (PH3) fumigation towards T. urticae might help officials to control them in quarantine purposes. PH3 fumigation controlled eggs (LC50; 0.158 mg/L), nymphs (LC50; 0.030 mg/L), and adults (LC50; 0.059 mg/L) of T. urticae, and EF effectively affected nymphs (LC50; 2.826 mg/L) rather than eggs (LC50; 6.797 mg/L) and adults (LC50; 5.836 mg/L). In a longer exposure time of 20 h, PH3 fumigation was 94.2-fold more effective tool for control of T. urticae than EF fumigant. EF and PH3 inhibited cytochrome c oxidase (COX) activity differently in both nymphs and adults of T. urticae. It confirmed COX is one of target sites of these fumigants in T. urticae and COX is involved in the respiratory chain as complex IV. Molecular approaches showed that EF fumigation completely down-regulated the expression of cox11 gene at the concentration of LC10 value, while PH3 up-regulated several genes greater than twofold in T. urticae nymphs treated with the concentration of LC50 value. These increased genes by PH3 fumigation are ndufv1, atpB, para, and ace, responsible for the expression of NADH dehydrogenase [ubiquinone] flavoprotein 1, ATP synthase, and acetylcholinesterase in insects, respectively. Lipidomic analyses exhibited a significant difference between two fumigants-exposed groups and the control, especially an ion with 815.46 m/z was analyzed less than twofold in the fumigants-treated group. It was identified as PI(15:1/18:3) and it may be used as a biomarker to EF and PH3 toxicity. These findings may contribute to set an effective control strategy on T. urticae by methyl bromide alternatives such as EF and PH3 because they have shared target sites on the respiratory chain in the pest.

Amyloid-β (Aβ) accumulation in the brain is a pathological feature of Alzheimer’s disease (AD) and enhancing Aβ clearance is a potential therapeutic strategy. Pioglitazone is a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist and is widely used to treat type 2 diabetes. We previously reported that low-dose pioglitazone increased the expression of low-density lipoprotein receptor-related protein 1 (LRP1), which upregulates the clearance of Aβ, using human brain microvascular endothelial cells. We investigated whether low-dose pioglitazone can rescue the pathological phenotype and memory impairment in senescence-accelerated mouse prone-8 (SAMP8) mice by increasing LRP1 levels. SAMP8 mice were treated with vehicle or pioglitazone in dosages of 2 or 5 mg/kg/day for 7 weeks. In the water maze test, 2 mg/kg/day of pioglitazone significantly attenuated the increased escape latency in SAMP8 mice (p = 0.026), while 5 mg/kg/day of treatment did not. Compared with vehicle treatment, the hippocampi of SAMP8 mice with 2 mg/kg/day of pioglitazone exhibited fewer Aβ deposits and reduced Aβ1–40 levels, along with elevated LRP1 expression (p = 0.005). Collectively, our results proposed that a new therapeutic application of the PPAR-γ agonist for AD treatment should be considered at a lower dose than the conventional dose used to treat diabetes.

A series of symmetric and nonsymmetric tetrahydroindenyl zirconium complexes was obtained by the reaction of ZrCl4 or (CpTMS)ZrCl3 with lithium salts of the corresponding tetrahydroindenes. Activated with methylalumoxane, these complexes exhibit high activity in polymerization of ethylene (up to 6.8∙106 g PE (mol Zr h)–1), as well as in copolymerization of ethylene and hex-1-ene (up to 8.6∙106 g PE (mol Zr h)–1).

Clinical trials suggested that the benefits of ezetimibe-statin combination therapy on major adverse cardiovascular events (MACE) might be greater in patients with diabetes. We aimed to investigate the differential association of ezetimibe-statin combination with incident MACE by presence of diabetes. In this retrospective cohort study, subjects treated with simvastatin 20 mg plus ezetimibe 10 mg (S + E) or simvastatin 20 mg alone (S) between 2005 and 2015 were 1:1 matched using propensity score as stratified by diabetes. Primary outcome was newly-developed MACE composed of cardiovascular death, ACS, coronary revascularization, or non-hemorrhagic stroke. During 5,077 and 12,439 person-years, the incidence rates of MACE were 24.9, 20.1, 35.3, and 22.8/1000 person-years among no diabetes S, no diabetes S + E, diabetes S, and diabetes S + E, respectively. Relative to no diabetes S, adjusted HR (aHR) for MACE in diabetes S was 1.23 (p = 0.086), whereas S + E was associated with a lower risk of MACE in both non-diabetic patients (aHR 0.76, p = 0.047) and diabetic patients (aHR 0.60, p = 0.007) with significant difference (relative excess risk due to interaction = −0.39, p = 0.044). In conclusion, reduction of MACE risk associated with ezetimibe plus simvastatin therapy relative to simvastatin alone was greater in patients with diabetes than in patients without diabetes.

Growth differentiation factor 15 (GDF15) is an endocrine hormone belonging to the TGFβ superfamily member. GDF15 administration or GDF15 overexpression has been reported to have anti-obesity and anti-diabetic effects. Although non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is frequently associated with obesity and insulin resistance, the functional role of endogenous GDF15 and therapeutic effect of GDF15 overexpression in NASH and related metabolic deterioration have not been evaluated. Here, we found that GDF15 expression was increased in the livers of NASH animal models and human subjects with NASH. Elevated expression of GDF15 was due to diet-induced hepatic endoplasmic reticulum (ER) stress. Gdf15-knockout mice exhibited aggravated NASH phenotypes such as increased steatosis, hepatic inflammation, fibrosis, liver injury, and metabolic deterioration. Furthermore, GDF15 directly suppressed expression of fibrosis-related genes and osteopontin (OPN), contributing factors for NASH-related fibrosis, in hepatic stellate cells in vitro and in the liver of mice in vivo. Finally, we found that GDF15-transgenic mice showed attenuation of NASH phenotypes and metabolic deterioration. Therefore, our results suggest that induction of endogenous GDF15 is a compensatory mechanism to protect against the progression of NASH and that GDF15 could be an attractive therapeutic candidate for treatment of NASH and NASH-related metabolic deterioration.

Skin auto-fluorescence (SAF) has generated broad interest about the prospects for non-invasive advanced glycation end product assessment and its direct interplay with the development of microvascular complications, but clinical application of the existing SAF measuring of non-palmoplantar sites in non-Caucasian subjects with dark skin type is still controversial. Here, we tested the diabetic complication screening performance of a novel SAF measuring system in Asian type 2 diabetes mellitus (T2DM) subjects. A total of 166 Korean patients with T2DM were enrolled in this study and palmoplantar SAF was measured by a newly developed transmission-geometry noninvasive optical system. We found that transmitted SAF values of palmoplantar sites, 1st dorsal interossei muscles of the hand, in a complication group were significantly higher than in a non-complication group while no differences were observed between the two groups in reflected SAF of non-palmoplantar sites. The transmitted SAF values of palmoplantar sites were dramatically increased in subjects with multiple complications and were tightly correlated with the duration of microvascular complications. In conclusion, the SAF measurement in the palmoplantar sites with a non-invasive transmission-geometry optical system provided better microvascular complication screening performance compared to the SAF measurement of non-palmoplantar sites specifically in Asian T2DM subjects.

Chlorpyrifos (CHL) is an organophosphate compound that is widely used as an insecticide. Due to its repeated use and high environmental residual property, CHL is frequently passed into aquatic environments by runoff. Consequently, there may be an adverse effect on aquatic vertebrate animals, including fish. Therefore, in this study, we assessed how CHL affected Japanese medaka (Oryzias latipes). The acute toxicity of CHL in adult fish after 96 h of exposure was determined to be 212.50, 266.79, and 412.28 μg L(-1) (LC25, LC50, and LC95, respectively). Acetylcholinesterase (AChE), glutathione S-transferase (GST), and carboxylesterase (CE) activities were obtained from the livers of dead or surviving fish, and the results showed 4.8-fold lower, 4.5-fold higher, and 18.6-fold lower activities for the AChE, GST, and CE, respectively, for 64-h exposure at a concentration of 400 μg L(-1) of CHL. In the embryo toxicity test, curved spines were observed in embryos that were exposed to CHL for 48 h in a concentration-dependent manner. With identification of biomarkers for CHL in the fish, two protein peaks, 5550.86 and 5639.79 m/z, were found to be upregulated. These two proteins can be used as protein biomarkers for CHL contamination in aquatic systems. A phosphatidyl choline with an m/z ratio of 556.32 dramatically decreased after CHL exposure in the fish; thus, it may be considered as a lipid biomarker for CHL. It is assumed as the first report to identify a phospholipid biomarker using a lipidomics approach in fish toxicology. Taken together, these results demonstrated the adverse effects of CHL on Japanese medaka and reveal several candidate biomarkers that can be used as diagnostic tools for determining CHL.

Background Although central fat is a well-known risk factor for cardiovascular disease (CVD) and cardiometabolic disorders, the effect of other regional fats or muscle distribution on CVD risk has not been fully investigated. Methods This was a cross-sectional study using nationally representative samples of 15,686 subjects from the 2008–2011 Korea National Health and Nutrition Examination Survey. Individual CVD risk was evaluated in adults aged ≥20 without prior CVD, using atherosclerotic cardiovascular disease (ASCVD) risk equations according to the 2013 ACC/AHA guidelines. Body composition was assessed by dual X-ray absorptiometry. Results Ratio of leg fat to total fat (LF/TF ratio) was the most predictive for CVD among body fat or muscle distribution parameters (AUC = 0.748, 95% CI 0.741–0.755). ASCVD risk score was gradually increased with decreased LF/TF ratio (P 10%) group compared to those in the highest tertile (OR = 6.25, 95% CI 5.60–6.98). Subjects in the lowest tertile showed increased risk of cardiometabolic risk factor components including obesity, hypertension, diabetes, dyslipidemia, chronic kidney disease, and albuminuria (OR range 2.57–11.24, all P

A simple palladium catalyst has mediated the facile formation of aroyl triflates — an extremely reactive class of electrophiles. These intermediates, generated in situ, enable the Friedel–Crafts acylation of traditionally unreactive arenes, addressing a significant gap in C–H carbonylation methodology.

Although 30–50 % of patients with brain tumors experience epileptic seizure as the presenting clinical symptom, and another 10–30 % are at risk for developing epilepsy in the later stages of the disease, the mechanisms of tumor-related epileptogenesis are poorly understood. We used magnetoencephalography (MEG) to investigate sensory evoked fields (SEFs) in patients with frontal lobe brain tumors as a means of evaluating the neuronal activity of peri-tumoral cortex. Twelve patients with frontal lobe brain tumors underwent MEG. We calculated the equivalent current dipole strength of two components of the primary sensory cortical response (N20m and P35m) and compared the P35m/N20m ratio in the tumor hemisphere vs. the normal hemisphere. There were two subsets of patients: group I, in which P35m/N20m was higher in the tumor hemisphere (n = 7), and group II, in which P35m/N20m was higher in the normal hemisphere (n = 5). We looked for associations between clinical factors and P35m/N20m within each group. All patients with seizure presentation were in group I, whereas only two patients without seizure presentation were in group I (Fisher exact test, p = 0.028). No other clinical factors were related to P35m/N20m. The mean ratio of P35m/N20m equivalent current dipole strength in patients with seizure presentation was 4.07 ± 2.38 in the tumor hemisphere and 2.00 ± 0.55 in the normal hemisphere. This difference was statistically significant (Mann-Whitney test, p = 0.030). The paradoxical increase in P35m/N20m in patients with seizure presentation suggests that decreased inhibitory neuronal activity is a potential cause of tumor-related epilepsy.

Snail belongs to the superfamily of zinc-finger transcription factors and plays a crucial role in processes regulating cell fate, such as the formation of mesoderm and initiation of epithelial-mesenchymal transition. We have previously discovered that Snail modulates adiponectin expression in 3T3-L1 cells during adipogenesis. In the present study, we elucidated the functional role of Snail in adipocyte differentiation and its underlying molecular mechanism. Snail expression was dramatically decreased during adipogenesis in 3T3-L1 cells. Overexpression of Snail blocked adipocyte differentiation by suppressing the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT-enhancer-binding protein alpha, while knockdown of Snail expression stimulated adipogenesis in 3T3-L1 cells. Chromatin immunoprecipitation assay and luciferase assay showed that Snail inhibits the transcriptional activity of the PPARγ gene by directly binding to the E-box motifs in the PPARγ promoter. Wnt10b induced phosphorylation of glycogen synthase kinase 3 beta (GSK3β), leading to inhibition of adipogenesis in 3T3-L1 cells in accordance with increased expression of Snail, whereas adipogenic capacity was restored in Snail siRNA-transfected preadipocytes. LiCl (a GSK3β inhibitor)-treated cells also showed increased expression of Snail, with a reduced adipogenic potential. Snail-overexpressing 3T3-F442A cells did not differentiate into mature adipocytes in immunodeficient nude mice. Taken together, Snail is a novel regulator of adipocyte differentiation, which acts by direct suppression of PPARγ expression. Our data also indicate that the expression of Snail is mediated by the Wnt-GSK3β signaling pathway.

Bariatric surgery effectively induces weight loss and resolves cardiovascular comorbidities in obese patients. We investigated cardiovascular and all-cause mortality in patients who underwent gastrectomies for early gastric cancer (EGC) and analyzed the changes in metabolic parameters after surgery. A total of 2,477 patients who underwent gastrectomies for EGC between 1995 and 2004 were enrolled in the study and followed for mortality through 2007. Standardized mortality ratios (SMRs) were calculated using sex- and age-matched mortality in the general Korean population in 2005. Effects of gastrectomy on changes in body weight and metabolic parameters were investigated in 51 of the patients before and after surgery. During the 15,096.4 person-years of follow-up, 244 deaths were recorded. The all-cause mortality was not significantly different from that of the general population (SMR [95 % confidence interval (CI)] = 1.01 [0.89 − 1.14]); however, cardiovascular mortality was significantly lower (SMR = 0.35 [0.22 − 0.53]). In the 51 patients included in the second part of the study, significant reductions in body weight and visceral fat areas occurred after surgery, regardless of whether the patients were previously obese. Triglycerides, LDL-cholesterol, and plasminogen activator inhibitor-1 levels were significantly decreased, whereas HDL-cholesterol and adiponectin levels were increased. Carotid intima-media thickness also was significantly decreased in previously obese and nonobese patients. Patients with EGC who undergo gastrectomy have a lower cardiovascular mortality but similar all-cause mortality as that of the general population. In these patients, a significant reduction in body weight and visceral fat after surgery may improve impaired lipid metabolism and prevent atherosclerotic changes.

Hemifacial spasm patients often suffer from non-motor symptoms such as tinnitus. These non-motor symptoms are known to be associated with changes in cortical activity. Magnetoencephalography (MEG) is a technique that can record brain activity noninvasively. To determine the usefulness of MEG in assessing changes in cortical activity associated with non-motor hearing symptoms in hemifacial spasm patients. We used MEG to evaluate the reactivity of the auditory cortex in 26 hemifacial spasm patients. We divided patients into a subjective tinnitus group (n = 10) and a non-tinnitus group (n = 16). The latency and amplitude of the most prominent deflection, N100m, was compared between the two groups. There was a significant difference in the pure tone audiogram on the spasm side compared with the non-spasm side. After stimulation on the spasm side, the amplitude of the N100m peak in the contralateral hemisphere was lower in the subjective tinnitus group than in the non-tinnitus group. Our results indicate that MEG can detect differences in cortical activity between hemifacial spasm patients with and without tinnitus. This suggests that MEG can identify changes in cortical activity associated with non-motor symptoms.

Glycated albumin (GA) is recognized as a reliable marker for short-term glycemic monitoring in diabetic patients. We investigated the clinical relevance of GA and the ratio of GA to glycated hemoglobin (A1c) in Korean type 2 diabetic patients. In this retrospective study, we compared A1c, GA, and the GA/A1c ratio and analyzed the relationship between glycemic indices and various parameters in 1,038 Korean type 2 diabetic patients. The patients were divided into two groups: a stably maintained A1c group whose A1c levels did not fluctuate by more than 0.5% for at least 6 months and an unstably maintained A1c group whose A1c levels fluctuated by more than 0.5%. Serum GA was strongly correlated with A1c in both groups. Fasting plasma glucose and postprandial glucose were correlated with GA in unstably maintained A1c group, whereas they were correlated with A1c in stably maintained A1c group. The GA/A1c ratio tended to increase as A1c increased. Postprandial glucose and body mass index affected the GA/A1c ratio. Our data show that serum GA may be a more useful glycation index than A1c for monitoring glycemic control in type 2 diabetic patients with fluctuating and poorly controlled glycemic excursions.

Glucose is a major source of metabolic fuel and lipid and protein syntheses. Transport of glucose into the cell is regulated by an action of glucose transport-associated transporters, especially solute carriers 2A (Slc2a, protein symbol GLUT). The present study was focused on examination of mRNA expression of various Slc2a isoforms in the epididymis during postnatal development. Total RNAs isolated from different epididymal segments (caput, corpus, and caudal epididymis) were utilized for real-time polymerase chain reaction analyses. Results showed that Slc2a 1, 3, 4, 5, and 8 were expressed in the entire epididymal regions. In addition, the abundance of these Slc2a isoforms' transcripts was different within each epididymal regions. Moreover, the present study showed differential expression of these Slc2a isoforms among different epididymal segments according to postnatal ages. The current study suggests that glucose transport in the epididymis via various Slc2a isoforms would be necessary for maintenance of the epididymal functions.

According to recent genome-wide association studies, a number of single nucleotide polymorphisms (SNPs) are reported to be associated with type 2 diabetes mellitus (T2DM). The aim of the present study was to investigate the association among the polymorphisms of SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1 and KCNQ1 and the risk of T2DM in the Korean population. This study was based on a multicenter case-control study, including 908 patients with T2DM and 502 non-diabetic controls. We genotyped rs13266634, rs1111875, rs10811661, rs4402960, rs8050136, rs734312, rs7754840 and rs2237892 and measured the body weight, body mass index and fasting plasma glucose in all patients and controls. The strongest association was found in a variant of CDKAL1 [rs7754840, odds ratio (OR) = 1.77, 95% CI = 1.50-2.10, p = 5.0 x 10(-11)]. The G allele of rs1111875 (OR = 1.43, 95% CI = 1.18-1.72, p = 1.8 x 10(-4)) in HHEX), the T allele of rs10811661 (OR = 1.47, 95% CI = 1.23-1.75, p = 2.1 x 10(-5)) in CDKN2A/B) and the C allele of rs2237892 (OR = 1.31, 95% CI = 1.10-1.56, p = 0.003) in KCNQ1 showed significant associations with T2DM. Rs13266634 (OR = 1.19, 95% CI = 1.00-1.42, p = 0.045) in SLC30A8 showed a nominal association with the risk of T2DM, whereas SNPs in IGF2BP2, FTO and WFS1 were not associated. In conclusion, we have shown that SNPs in HHEX, CDKN2A/B, CDKAL1, KCNQ1 and SLC30A8 confer a risk of T2DM in the Korean population.

Background The heart requires constant sources of energy mostly from free fatty acids (FFA) and glucose. The alteration in myocardial substrate metabolism occurs in the heart of diabetic patients, but its specific association with other metabolic variables remains unclear. We aimed to evaluate glucose uptake in hearts of subjects with normal glucose tolerance (NGT), prediabetes, and type 2 diabetes mellitus (T2DM) using [18F]-fluorodeoxyglucose-positron emission tomography (18FDG-PET) in association with visceral and subcutaneous adiposity, and metabolic laboratory parameters. Methods A total of 346 individuals (NGT, n = 76; prediabetes, n = 208; T2DM, n = 62) in a health promotion center of a tertiary hospital were enrolled. The fasting myocardial glucose uptake, and visceral and subcutaneous fat areas were evaluated using 18FDG-PET and abdominal computed tomography, respectively. Results Myocardial glucose uptake was significantly decreased in subjects with T2DM compared to the NGT or prediabetes groups (p for trend = 0.001). Multivariate linear regression analyses revealed that visceral fat area (β = −0.22, p = 0.018), fasting FFA (β = −0.39, p

Aims/hypothesis: Obesity increases the risk of developing major diseases such as diabetes and cardiovascular disease. Adipose tissue, particularly adipocytes, may play a major role in the development of obesity and its comorbidities. The aim of this study was to characterise, in adipocytes from obese people, the most differentially expressed genes that might be relevant to the development of obesity. Methods: We carried out microarray gene profiling of isolated abdominal subcutaneous adipocytes from 20 non-obese (BMI 25±3 kg/m2) and 19 obese (BMI 55± 8 kg/m2) non-diabetic Pima Indians using Affymetrix HG-U95 GeneChip arrays. After data analyses, we measured the transcript levels of selected genes based on their biological functions and chromosomal positions using quantitative real-time PCR. Results: The most differentially expressed genes in adipocytes of obese individuals consisted of 433 upregulated and 244 downregulated genes. Of these, 410 genes could be classified into 20 functional Gene Ontology categories. The analyses indicated that the inflammation/immune response category was over-represented, and that most inflammation-related genes were upregulated in adipocytes of obese subjects. Quantitative real-time PCR confirmed the transcriptional upregulation of representative inflammation-related genes (CCL2 and CCL3) encoding the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein 1α. The differential expression levels of eight positional candidate genes, including inflammation-related THY1 and C1QTNF5, were also confirmed. These genes are located on chromosome 11q22-q24, a region with linkage to obesity in the Pima Indians. Conclusions/interpretation: This study provides evidence supporting the active role of mature adipocytes in obesity-related inflammation. It also provides potential candidate genes for susceptibility to obesity.

Whole body insulin resistance results largely from impaired insulin-stimulated glucose disposal into skeletal muscle. We carried out muscle gene expression profiling to identify differentially expressed genes associated with insulin resistance.Skeletal muscle total RNA samples from six pairs of non-diabetic insulin-resistant and insulin-sensitive Pima Indians matched for percent body fat were analyzed by DDPCR with 90 primer combinations. The mRNA expression concentrations of selected 13 known genes and four expressed sequences tags were measured by quantitative real-time RT-PCR in 50 non-diabetic Pima subjects.From over 6500 displayed DDPCR cDNA bands, 36 of the most differentially expressed cDNAs were identified, revealing 29 unique sequences: 16 known genes, 10 expressed sequences tags and three unknown transcripts. Multiple regression analyses indicated that whole body insulin-mediated glucose disposal rates of the subjects, independent of age, sex, and percent body fat, were negatively correlated with mRNA concentrations of an EST (DD23; r=-0.38, p=0.007), ATP1A2 (r=-0.27, p=0.05), MAP2K4 (r=-0.34, p=0.02), and PRPSAP1 (r=-0.37, p=0.008). Transcript concentrations of DD23 (r=0.27, p=0.05) and MTND4 (r=-0.29, p=0.05) were correlated with plasma insulin concentration, independent of age, sex, and percent body fat.Altered expression concentrations of these genes might be causes or consequences of insulin resistance, and these genes serve as candidate susceptibility genes for insulin resistance.

The reaction characteristics of molten Au/Sn eutectic solder with potential diffusion-barrier materials of optoelectronic packages were investigated. The characteristics were studied by reflowing the solder on Pt, Ni, and Co plates, respectively, and by measuring the thickness of the reaction product. In addition, the dissolution rate of Pt into the solder was measured. The results indicated that Pt, which is commonly used as the diffusion-barrier layer in the under-bump metallurgy (UBM) of optoelectronic packages, reacts readily with the molten solder, resulting in discontinuous reaction products at the solder/Pt interface. Cobalt, on the other hand, reacted with the solder at an order of magnitude slower rate than that of Pt and provided an effective barrier against the reaction with the solder.

Chip-on-glass (COG) mounting of area array electronic packages was attempted by heating the rear surfrace of a contact pad film deposited on a glass substrate. The pads consisted of an adhesion (i.e., Cr or Ti) and a top coating layer (i.e., Ni or Cu) was heated by an UV laser beam transmitted through the glass substrate. The laser energy absorbed on the pad raised the temperature of a solder ball which was in physical contact with the pad, forming a reflowed solder bump. The effects of the adhesion and top coating layer on the laser reflow soldering were studied by measuring the temperature profile of the ball during the laser heating process. The results were discussed based on the measurement of reflectivity of the adhesion layers. In addition, the microsctructures of solder bumps and their mechanical properties were examined.

The thermodynamic stability of the solder channels at a scalloplike Cu6Sn5 layer formed between Sn-containing solders and Cu substrate was evaluated by studying the penetration behavior of the liquid solders into the grain boundaries of a Cu6Sn5 substrate. The orientational relationship between the grains of the Cu6Sn5 layer formed during reflow soldering was also analyzed using the electron backscattered diffraction technique. The results showed that liquid solders penetrate into the grain boundaries at an order of faster speed than the growth rate of the layer, which provided a direct evidence of thermodynamic stability of the channel.

In an attempt to develop a fluxless reflow solder bumping process, the effects of processing variables, which include energy input rate and time, and the shape of solder disk on the microstructure of the solder/Cu pad interface and the shear strength of the joints were investigated. It was demonstrated that a proper combination of the variables could lead to the formation of a spherical solder bump with shear strength comparable to that formed via the conventional reflow soldering process. In addition, the kinetics of Cu pad dissolution into the solder during laser heating was modeled numerically to elucidate intermetallic formation mechanism at the solder/Cu pad interface.

In an attempt to develop a thermally stable solder system, an in-situ Pb-Sn solder composite reinforced with Cu6Sn5 dispersoids was investigated for its thermal stability. The stability was evaluated mainly by measuring the growth rate of intermetallics at in-situ composite solder/BLM interface as a function of the number of reflow soldering cycles and aging time. The rates were compared with those of the eutectic Pb-Sn and Sn-Ag solders. After the thermal treatments, the solder joints were tested for their shear strengths. The results indicated that the in-situ composite solder has a higher shear strength and better thermal stability than the eutectic Pb-Sn solder.

The rate-controlling reactions in the combustion synthesis of TiAl were studied using DTA and reaction furnace. It was demonstrated that the rate-controlling reactions vary with the combustion temperature. The effects of processing parameters on the homogeneity, densifieation, and microstructures of the products reacted in a hot press were investigated. The processing parameters include heating rate, thermal insulating layer between the mold and the sample, and heat treating temperatures. It is shown that that proper combustions of processing conditions and heat treatment of the combustion reaction products could lead to homogeneous and dense microstructures with duplex, or fully lamellar structures in a single processing step.

Effects Cu and Ni additions on Au embrittlement of eutectic Sn–Pb solder interconnections during a solid-state aging treatment were evaluated using a ball shear testing method. The addition resulted in a formation of Au-containing ternary intermetallic compounds, either Au–Sn–Cu or Au–Sn–Ni phase, inside the solder matrix during aging treatment. The fracture energy of the solder interconnection containing 2.9 wt% Cu remained almost the same up to 200 h of aging treatment at 150 °C, demonstrating the possibility of suppressing the Au embrittlement by forming ternary intermetallic phases inside the solder matrix.