Despite the emerging importance of fibroblast growth factor 21 (FGF21) as a metabolic hormone regulating energy balance, its direct effects on renal function remain unexplored. FGF21 was injected ip ...daily for 12 weeks into db/db mice. Compared with control vehicle injection, FGF21 treatment significantly improved lipid profiles and insulin resistance and resulted in significantly higher serum adiponectin levels. In contrast, serum insulin and 8-isoprostane levels were significantly decreased. Interestingly, FGF21 and its receptor components in the kidneys were found to be significantly up-regulated in db/db mice, which suggests an FGF21-resistant state. FGF21 treatment significantly down-regulated FGF21 receptor components and activated ERK phosphorylation. FGF21 administration also markedly decreased urinary albumin excretion and mesangial expansion and suppressed profibrotic molecule synthesis. Furthermore, FGF21 improved renal lipid metabolism and oxidative stress injury. In cultured renal cells, FGF21 was mainly expressed in mesangial cells, and knockdown of FGF21 expression by stealth small interfering RNA further aggravated high-glucose-induced profibrotic cytokine synthesis in mesangial cells. Our results suggest that FGF21 improves insulin resistance and protects against renal injury through both improvement of systemic metabolic alterations and antifibrotic effects in type 2 diabetic nephropathy. Targeting FGF21 could therefore provide a potential candidate approach for a therapeutic strategy in type 2 diabetic nephropathy.
Chronic inflammation caused by high glucose and high free fatty acid (FFA) concentrations is a major contributor to the pathogenesis of type 2 diabetes. Recent evidence suggests that activation of ...Toll-like receptor (TLR) signaling induces peripheral insulin resistance and mediates central insulin and leptin resistance. In this study, we investigated the renal effects of TLR4 signaling blockade in type 2 diabetic mice. Eight-week-old db/db mice were treated for 12 weeks with (S,R)-3-phenyl-4,5-dihydro-5-isoxasole acetic acid (GIT27), which targets macrophages through the inhibition of TLR4- and TLR2/6-mediated signaling pathways. Although GIT27 treatment improved glycemic control and insulin tolerance, which is associated with a lower lipid profile, it did not impact body weight or food consumption. GIT27 treatment also markedly decreased urinary albumin excretion, decreased proinflammatory cytokine synthesis, improved tissue lipid metabolism, induced oxidative stress, and improved glomerulosclerosis compared with the control db/db group. In cultured podocytes and adipocytes, high glucose levels with FFA stimulation increased TLR4 expression and proinflammatory cytokine synthesis, but the effects were abolished by GIT27 treatment. In addition, knockdown of TLR4 expression by stealth small interfering RNA abolished FFA-induced proinflammatory cytokine synthesis in cultured podocytes. In conclusion, our results suggest that GIT27 treatment improves insulin resistance and protects against the renal injury that occurs in type 2 diabetic nephropathy through both metabolic and antiglomerulosclerotic mechanisms. These results suggest that TLR pathway inhibition might play a direct protective role in diabetic kidney disease.
In this paper, the prediction skills of five ensemble methods for temperature and precipitation are discussed by considering 20 yr of simulation results (from 1989 to 2008) for four regional climate ...models (RCMs) driven by NCEP–Department of Energy and ECMWF Interim Re-Analysis (ERA-Interim) boundary conditions. The simulation domain is the Coordinated Regional Downscaling Experiment (CORDEX) for East Asia, and the number of grid points is 197 × 233 with a 50-km horizontal resolution. Three new performance-based ensemble averaging (PEA) methods are developed in this study using 1) bias, root-mean-square errors (RMSEs) and absolute correlation (PEA_BRC), RMSE and absolute correlation (PEA_RAC), and RMSE and original correlation (PEA_ROC). The other two ensemble methods are equal-weighted averaging (EWA) and multivariate linear regression (Mul_Reg). To derive the weighting coefficients and cross validate the prediction skills of the five ensemble methods, the authors considered 15-yr and 5-yr data, respectively, from the 20-yr simulation data. Among the five ensemble methods, the Mul_Reg (EWA) method shows the best (worst) skill during the training period. The PEA_RAC and PEA_ROC methods show skills that are similar to those of Mul_Reg during the training period. However, the skills and stabilities of Mul_Reg were drastically reduced when this method was applied to the prediction period. But, the skills and stabilities of PEA_RAC were only slightly reduced in this case. As a result, PEA_RAC shows the best skill, irrespective of the seasons and variables, during the prediction period. This result confirms that the new ensemble method developed in this study, PEA_RAC, can be used for the prediction of regional climate.
A memory cell consisting of a Pt/VO2/Pt switch element and a Pt/NiO/Pt memory element connected in series. By applying a voltage higher than Vth of 0.6 V, the switch element reaches the on state and ...the cell can be accessed. Since reset and set voltages are higher than Vth, information can be written by simply applying an appropriate voltage to a selected cell. By applying a voltage lower than Vth to the other cells, we can keep the other cells in the off state and prevent interference between the selected cell and the others.
The endocannabinoid system is important in the pathogenesis of obesity-related metabolic disorders. However, the effect of inhibiting the endocannabinoid system in type 2 diabetic nephropathy is ...unclear. Therefore, we examined the effect of the cannabinoid (CB)1 receptor antagonist, SR141716, on insulin resistance and diabetic nephropathy in db/db mice. Six-week-old db/db mice were treated with the CB1-specific antagonist SR141716 (10 mg/kg·d) for 3 months. Treatment with SR141716 significantly improved insulin resistance and lipid abnormalities. Concomitantly, CB1 antagonism improved cardiac functional and morphological abnormality, hepatic steatosis, and phenotypic changes of adipocytes into small differentiated forms, associated with increased adiponectin expression and decreased lipid hydroperoxide levels. CB1 receptor was overexpressed in diabetic kidneys, especially in podocytes. Treatment with the SR141716 markedly decreased urinary albumin excretion and mesangial expansion and suppressed profibrotic and proinflammatory cytokine synthesis. Furthermore, SR141716 improved renal lipid metabolism and decreased urinary 8-isoprostane levels, renal lipid hydroperoxide content, and renal lipid content. In cultured podocytes, high-glucose stimulation increased CB1 receptor expression, and SR141716 treatment abolished high-glucose-induced up-regulation of collagen and plasminogen activator inhibitor-1 synthesis. Additionally, knockdown of CB1 receptor expression by stealth small interfering RNA abolished high-glucose-induced sterol-regulatory element-binding protein-1 expression in podocytes. These findings suggest that CB1 blockade improves insulin resistance and protect against renal injury through both metabolic and antifibrotic effects in type 2 diabetic nephropathy. Targeting CB1 blockade could therefore provide a new therapeutic target to prevent type 2 diabetic nephropathy.
The multiparametric imaging can show us different aspects of tumor behavior and may help differentiation of tumor recurrence from treatment related change. Our aim was to differentiate tumor ...progression from pseudoprogression in patients with glioblastoma by using multiparametric histogram analysis of 2 consecutive MR imaging studies with relative cerebral blood volume and ADC values.
Thirty-five consecutive patients with glioblastoma with new or increased size of enhancing lesions after concomitant chemoradiation therapy following surgical resection were included. Combined histograms were made by using the relative cerebral blood volume and ADC values of enhancing areas for initial and follow-up MR imaging, and subtracted histograms were also prepared. The histogram parameters between groups were compared. The diagnostic accuracy of tumor progression based on the histogram parameters of initial and follow-up MR imaging and subtracted histograms was compared and correlated with overall survival.
Twenty-four pseudoprogressions and 11 tumor progressions were determined. Diagnosis based on the subtracted histogram mode with a multiparametric approach was more accurate than the diagnosis based on the uniparametric approach (area under the receiver operating characteristic curve of 0.877 versus 0.801), with 81.8% sensitivity and 100% specificity. A high mode of relative cerebral blood volume on the subtracted histogram by using a multiparametric approach (relative cerebral blood volume ×ADC) was the best predictor of true tumor progression (P < .001) and worse survival (P = .003).
Multiparametric histogram analysis of posttreatment glioblastoma was useful to predict true tumor progression and worse survival.
We aimed to compare tissue-specific expression profiles and biological pathways of RNA from amniocytes and amniotic fluid supernatant (AFS) from second-trimester pregnancies by using transcriptome ...analysis. Additionally, we wanted to explore whether cell-free RNA from AFS exhibits a unique gene expression signature that more adequately reflects the fetal developmental process than amniocyte RNA.
Amniotic fluid samples were prospectively collected in the second trimester of pregnancy from euploid fetuses. Total RNA was extracted from amniocytes and AFS and hybridized to Affymetrix GeneChip Human Arrays. Significantly differentially expressed transcripts between amniocytes and AFS were obtained by using Welch's t-test. Unsupervised hierarchical clustering was used to visualize overall expression characteristics and differences in transcripts between AFS and amniocytes. The biological functions of selected genes were analyzed using various online Gene Ontology databases.
A total of 3,072 and 15,633 transcripts were detected in the second-trimester AFS and amniocytes, respectively. Hierarchical clustering revealed differential transcript expression between AFS and amniocytes. We found 353 genes that were specifically enriched in the AFS only, and tissue expression analysis showed enrichment of brain-specific genes in the AFS. Biological pathway analysis revealed that AFS-specific transcripts were mainly involved in embryonic development, cardiovascular development, and cellular morphology pathways.
This study demonstrated differential tissue-specific gene expression profiles and biological pathways between AFS and amniocytes. The results suggested that AFS is the preferred RNA source to investigate potential biomarkers of fetal neurodevelopment.
Background and purpose
The rate at which the chance of a good outcome of endovascular stroke therapy (EVT) decays with time when eligible patients are selected by baseline diffusion‐weighted magnetic ...resonance imaging (DWI‐MRI) and whether ischaemic core size affects this rate remain to be investigated.
Methods
This study analyses a prospective multicentre registry of stroke patients treated with EVT based on pretreatment DWI‐MRI that was categorized into three groups: small Diffusion‐Weighted Imaging Alberta Stroke Program Early Computed Tomography Score (DWI‐ASPECTS) (8–10), moderate (5–7) and large (<5) cores. The main outcome was a good outcome at 90 days (modified Rankin Scale 0–2). The interaction between onset‐to‐groin puncture time (OTP) and DWI‐ASPECTS categories regarding functional outcomes was investigated.
Results
Ultimately, 985 patients (age 69 ± 11 years; male 55%) were analysed. Potential interaction effects between the DWI‐ASPECTS categories and OTP on a good outcome at 90 days were observed (Pinteraction = 0.06). Every 60‐min delay in OTP was associated with a 16% reduced likelihood of a good outcome at 90 days amongst patients with large cores, although no associations were observed amongst patients with small to moderate cores. Interestingly, the adjusted rates of a good outcome at 90 days steeply declined between 65 and 213 min of OTP and then remained smooth throughout 24 h of OTP (Pnonlinearity = 0.15).
Conclusions
Our study showed that the probability of a good outcome after EVT nonlinearly decreased, with a steeper decline at earlier OTP than at later OTP. Discrepant effects of OTP on functional outcomes by baseline DWI‐ASPECTS categories were observed. Thus, different strategies for EVT based on time and ischaemic core size are warranted.
SiC-based avalanche photodiodes (APDs) are the preferred devices for use in high-sensitivity UV detectors. However, the defect densities on the surface or in the bulk of the SiC epitaxial layer limit ...the performance of APDs. In this study, the effect of defects resulting in electrical fatigue in 4H-SiC APDs on device performance was analyzed. Further, fast and efficient defect analysis and detection methods based on laser scanning confocal microscopy are proposed for high-performance APD fabrication. Experimental results show a correlation between the electrical transport and optical properties with respect to the defect behavior in the active and non-active area based on the physical morphology.
An 8 Gb 4-stack 3-D DDR3 DRAM with through-Si-via is presented which overcomes the limits of conventional modules. A master-slave architecture is proposed which decreases the standby and active power ...by 50 and 25%, respectively. It also increases the I/O speed to > 1600 Mb/s for 4 rank/module and 2 module/channel case since the master isolates all chip I/O loadings from the channel. Statistical analysis shows that the proposed TSV check and repair scheme can increase the assembly yield up to 98%. By providing extra VDD/VSS edge pads, power noise is reduced to < 100 mV even if all 4 ranks are refreshed every clock cycle consecutively.
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