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Purpose To demonstrate robust myelin water fraction (MWF) mapping using an artificial neural network (ANN) with multi-echo gradient-echo (GRE) signal. Methods Multi-echo gradient-echo signals simulated with a three-pool exponential model were used to generate the training data set for the ANN, which was designed to yield the MWF. We investigated the performance of our proposed ANN for various conditions using both numerical simulations and in vivo data. Simulations were conducted with various SNRs to investigate the performance of the ANN. In vivo data with high spatial resolutions were applied in the analyses, and results were compared with MWFs derived by the nonlinear least-squares algorithm using a complex three-pool exponential model. Results The network results for the simulations show high accuracies against noise compared with nonlinear least-squares MWFs: RMS-error value of 5.46 for the nonlinear least-squares MWF and 3.56 for the ANN MWF at an SNR of 150 (relative gain = 34.80%). These effects were also found in the in vivo data, with reduced SDs in the region-of-interest analyses. These effects of the ANN demonstrate the feasibility of acquiring high-resolution myelin water images. Conclusion The simulation results and in vivo data suggest that the ANN facilitates more robust MWF mapping in multi-echo gradient-echo sequences compared with the conventional nonlinear least-squares method. more...

Multi-echo gradient-echo (mGRE)-based myelin water fraction (MWF) mapping is a promising myelin water imaging (MWI) modality but is vulnerable to noise and artifact corruption. The linear dimensionality reduction (LDR) method has recently shown improvements with regard to these challenges. However, the magnitude value based low rank operators have been shown to misestimate the MWF for regions with [Formula: see text] anisotropy. This paper presents a nonlinear dimensionality reduction (NLDR) method to estimate the MWF map better by encouraging nonlinear low dimensionality of mGRE signal sources. Specifically, we implemented a fully connected deep autoencoder to extract the low-dimensional features of complex-valued signals and incorporated a sparse regularization to separate the anomaly sources that do not reside in the low-dimensional manifold. Simulations and in vivo experiments were performed to evaluate the accuracy of the MWF map under various situations. The proposed NLDR-based MWF improves the accuracy of the MWF map over the conventional nonlinear least-squares method and the LDR-based MWF and maintains robustness against noise and artifact corruption. more...

An increase in hyperpolarized (HP) [1‐13C]lactate production has been suggested as a biomarker for cancer occurrence as well as for response monitoring of cancer treatment. Recently, the use of metformin has been suggested as an anticancer or adjuvant treatment. By regulating the cytosolic NAD+/NADH redox state, metformin stimulates lactate production and increases the HP [1‐13C]lactate conversion rate in the kidney, liver, and heart. In general, increased HP [1‐13C]lactate is regarded as a sign of cancer occurrence or tumor growth. Thus, the relationship between the tumor suppression effect of metformin and the change in metabolism monitored by HP [1‐13C]pyruvate MRS in cancer treatment needs to be investigated. The present study was performed using a brain metastasis animal model with MDA‐MB‐231(BR)‐Luc breast cancer cells. HP [1‐13C]pyruvate MRS, T 2‐weighted MRI, and bioluminescence imaging were performed in groups treated with metformin or adjuvant metformin and radiation therapy. Metformin treatment alone did not display a tumor suppression effect, and the HP [1‐13C]lactate conversion rate increased. In radiation therapy, the HP [1‐13C]lactate conversion rate decreased with tumor suppression, with a p‐value of 0.028. In the adjuvant metformin and radiation treatment, the tumor suppression effect increased, with a p‐value of 0.001. However, the apparent HP [1‐13C]lactate conversion rate (K pl) was observed to be offset by two opposite effects: a decrease on radiation therapy and an increase caused by metformin treatment. Although HP [1‐13C]pyruvate MRS could not evaluate the tumor suppression effect of adjuvant metformin and radiation therapy due to the offset phenomenon, metabolic changes following only metformin pre‐treatment could be monitored. Therefore, our results indicate that the interpretation of HP [1‐13C]pyruvate MRS for response monitoring of cancer treatment should be carried out with caution when metformin is used as an adjuvant cancer therapy., 1. Metformin increased HP [1‐13C] lactate/pyruvate (K pl) without tumor suppression. 2. Adjuvant metformin sensitized the radiation‐induced tumor suppression effect. However, the K pl was observed to be offset by two opposite effects: a decrease on radiation therapy and an increase caused by metformin treatment. more...

Hypothalamic feeding circuits have been identified as having innate synaptic plasticity, mediating adaption to the changing metabolic milieu by controlling responses to feeding and obesity. However, less is known about the regulatory principles underlying the dynamic changes in agouti-related protein (AgRP) perikarya, a region crucial for gating of neural excitation and, hence, feeding. Here we show that AgRP neurons activated by food deprivation, ghrelin administration, or chemogenetics decreased their own inhibitory tone while triggering mitochondrial adaptations in neighboring astrocytes. We found that it was the inhibitory neurotransmitter GABA released by AgRP neurons that evoked this astrocytic response; this in turn resulted in increased glial ensheetment of AgRP perikarya by glial processes and increased excitability of AgRP neurons. We also identified astrocyte-derived prostaglandin E(2), which directly activated — via EP2 receptors — AgRP neurons. Taken together, these observations unmasked a feed-forward, self-exciting loop in AgRP neuronal control mediated by astrocytes, a mechanism directly relevant for hunger, feeding, and overfeeding. more...

In the presence of high abundance of exogenous fatty acids, cells either store fatty acids in lipid droplets or oxidize them in mitochondria. In this study, we aimed to explore a novel and direct role of mitochondrial fission in lipid homeostasis in HeLa cells. We observed the association between mitochondrial morphology and lipid droplet accumulation in response to high exogenous fatty acids. We inhibited mitochondrial fission by silencing dynamin-related protein 1(DRP1) and observed the shift in fatty acid storage-usage balance. Inhibition of mitochondrial fission resulted in an increase in fatty acid content of lipid droplets and a decrease in mitochondrial fatty acid oxidation. Next, we overexpressed carnitine palmitoyltransferase-1 (CPT1), a key mitochondrial protein in fatty acid oxidation, to further examine the relationship between mitochondrial fatty acid usage and mitochondrial morphology. Mitochondrial fission plays a role in distributing exogenous fatty acids. CPT1A controlled the respiratory rate of mitochondrial fatty acid oxidation but did not cause a shift in the distribution of fatty acids between mitochondria and lipid droplets. Our data reveals a novel function for mitochondrial fission in balancing exogenous fatty acids between usage and storage, assigning a role for mitochondrial dynamics in control of intracellular fuel utilization and partitioning. more...

The hypothalamic orexigenic Agouti-related peptide (AgRP)-expressing neurons are crucial for the regulation of whole-body energy homeostasis. Here, we show that fasting-induced AgRP neuronal activation is associated with dynamin-related peptide 1 (DRP1)-mediated mitochondrial fission and mitochondrial fatty acid utilization in AgRP neurons. In line with this, mice lacking Dnm1l in adult AgRP neurons (Drp1 cKO) show decreased fasting- or ghrelin-induced AgRP neuronal activity and feeding and exhibited a significant decrease in body weight, fat mass, and feeding accompanied by a significant increase in energy expenditure. In support of the role for mitochondrial fission and fatty acids oxidation, Drp1 cKO mice showed attenuated palmitic acid-induced mitochondrial respiration. Altogether, our data revealed that mitochondrial dynamics and fatty acids oxidation in hypothalamic AgRP neurons is a critical mechanism for AgRP neuronal function and body-weight regulation. more...

The bioenergetic function of mitochondrial fission is associated with uncoupled respiration or elimination of damaged mitochondria to maintain a healthy mitochondrial population. In the presence of a high abundance of exogenous fatty acids, cells can either store fatty acids in lipid droplets or oxidize them in mitochondria. Even though carnitine palmitoyltransferase-1 (CPT1) controls the respiratory capacity of mitochondria in fatty acid oxidation, we observed that it did not dictate the balance of storage and usage of lipids in HeLa cells. On the other hand, inhibition of mitochondrial fission by silencing dynamic-related protein 1 (DRP1) resulted in an increase in fatty acid content of lipid droplets and a decrease in fatty acid oxidation. Mitochondrial fission was not only reflective of the amount of exogenous fatty acid being processed by mitochondria, but also found to be actively involved in the distribution of fatty acids between mitochondria and lipid droplets. Our data reveals a novel function for mitochondrial fission in balancing exogenous fatty acids between usage and storage, assigning a role for mitochondrial dynamics in control of intracellular fuel utilization and partitioning. more...

Purpose To test the feasibility of using the SPICE (SPectroscopic Imaging by exploiting spatiospectral CorrElation) technique, which uses the partial separability of spectroscopic data, for high resolution hyperpolarized (HP) 13 C spectroscopic imaging. Methods Numerical simulations were performed to investigate the impact of transient HP signals on SPICE reconstruction. Furthermore, spectroscopic imaging exams from SPICE and conventional EPSI (echo-planar spectroscopic imaging) were simulated for comparison. For in vivo experiments, HP 13 C SPICE was performed in a mouse kidney by means of the injection of HP [1-13 C] pyruvate at 9.4T. Results The variation of lactate/pyruvate from the simulated SPICE was less than 4% under various factors that affect the transient HP signal, suggesting that the impact is negligible. We found that while HP 13 C EPSI was limited to the low signal-to-noise ratio (SNR) of lactate, these limitations were mitigated through HP 13 C SPICE, facilitating the improved SNR of lactate and the distinction of tissues. Acquisition of a high resolution HP 13 C spectroscopic image was possible for the in vivo experiments. With the fine structural information, the acquired image showed higher signal of pyruvate and lactate in the renal cortices than in the medullas, which is known to be attributed to higher activity of lactate dehydrogenase. Conclusion The feasibility of HP 13 C SPICE was investigated. Simulation studies were conducted and in vivo experiments were performed in the mouse kidney at 9.4T. Results confirmed that a high resolution HP 13 C spectroscopic image with adequate spectral resolution can be obtained. Magn Reson Med 80:703-710, 2018. © 2018 International Society for Magnetic Resonance in Medicine. more...

Cleavage stimulation factor (CstF) is a highly conserved protein complex composed of three subunits that recognizes G/U-rich sequences downstream of the polyadenylation signal of eukaryotic mRNAs. While CstF has been identified over 25 years ago, the architecture and contribution of each subunit to RNA recognition have not been fully understood. In this study, we provide a structural basis for the recruitment of CstF-50 to CstF via interaction with CstF-77 and establish that the hexameric assembly of CstF creates a high affinity platform to target various G/U-rich sequences. We further demonstrate that CstF-77 boosts the affinity of the CstF-64 RRM to the RNA targets and CstF-50 fine tunes the ability of the complex to recognize G/U sequences of certain lengths and content. more...

This study aims to investigate the feasibility of dynamic hyperpolarized 13 C MR spectroscopic imaging (MRSI) using the SPectroscopic Imaging by exploiting spatiospectral CorrElation (SPICE) technique and an estimation of the spatially resolved conversion constant rate (kpl ). An acquisition scheme comprising a single training dataset and several imaging datasets was proposed considering hyperpolarized 13 C circumstances. The feasibility and advantage of the scheme were investigated in two parts: (a) consistency of spectral basis over time and (b) accuracy of the estimated kpl . The simulations and in vivo experiments support accurate kpl estimation with consistent spectral bases. The proposed method was implemented in an enzyme phantom and via in vivo experiments. In the enzyme phantom experiments, spatially resolved homogeneous kpl maps were observed. In the in vivo experiments, normal diet (ND) mice and high-fat diet (HFD) mice had kpl (s-1 ) values of medullar (ND: 0.0119 ± 0.0022, HFD: 0.0195 ± 0.0005) and cortical (ND: 0.0148 ±0.0023, HFD: 0.0224 ±0.0054) regions which were higher than vascular (ND: 0.0087 ±0.0013, HFD: 0.0132 ±0.0050) regions. In particular, the kpl value in the medullar region exhibited a significant difference between the two diet groups. In summary, the feasibility of using modified SPICE for dynamic hyperpolarized 13 C MRSI was demonstrated via simulations and in vivo experiments. The consistency of spectral bases over time and the accuracy of the estimated kpl values validate the proposed acquisition scheme, which comprises only a single training dataset. The proposed method improved the spatial resolution of dynamic hyperpolarized 13 C MRSI, which could be used for kpl estimation using high signal-to-noise ratio spectral bases. more...

This study aims to investigate the feasibility of dynamic hyperpolarized

This paper develops a model of a competitive search credit market under hidden information and limited commitment. Using the model, it provides a theoretical account that links time delays and costs in financial intermediation as well as lack of collateral to the distribution of credit supply and interest rate spreads. The link sheds light on and explains the possibility of pure credit rationing due to the credit frictions. This paper also demonstrates the possibility of contract dispersion among homogeneous borrowers. more...

Purpose To optimize and investigate the influence of bipolar gradients for flow suppression in metabolic quantification of hyperpolarized 13C chemical shift imaging (CSI) of mouse liver at 9.4 T. Methods The trade-off between the amount of flow suppression using bipolar gradients and T2* effect from static spins was simulated. A free induction decay CSI sequence with alternations between the flow-suppressed and non–flow-suppressed acquisitions for each repetition time was developed and was applied to liver tumor–bearing mice via injection of hyperpolarized [1-13C] pyruvate. Results The in vivo results from flow suppression using the velocity-optimized bipolar gradient were comparable with the simulation results. The vascular signal was adequately suppressed and signal loss in stationary tissue was minimized. Application of the velocity-optimized bipolar gradient to tumor-bearing mice showed reduction in the vessel-derived pyruvate signal contamination, and the average lactate/pyruvate ratio increased by 0.095 (P more...

Higher dietary intakes of saturated fatty acid increase the risk of developing Alzheimer’s disease and dementia, and even in people without diabetes higher glucose levels may be a risk factor for dementia. The mechanisms causing neuronal dysfunction and dementia by consuming high-fat diet degrading the integrity of the blood-brain barrier (BBB) has been suggested but are not yet fully understood, and metabolic state of the brain by this type of insult is still veiled. The objective of this study was to investigate the effect of high-fat diet on the brain metabolism by a multimodal imaging method using the hyperpolarizedcarbon 13 (13C)-pyruvate magnetic resonance (MR) spectroscopy and dynamic contrast-enhanced MR imaging in conjunction with the biochemical assay and the behavior test in a mouse model fed high-fat diet (HFD). In mice were fed 60% HFD for 6 months, hyperpolarized [1-13C] pyruvate MR spectroscopy showed decreased perfusion (p more...

Summary Despite the known causality of copy-number variations (CNVs) to human neurodevelopmental disorders, the mechanisms behind each gene’s contribution to the constellation of neural phenotypes remain elusive. Here, we investigated the 7q11.23 CNV, whose hemideletion causes Williams syndrome (WS), and uncovered that mitochondrial dysfunction participates in WS pathogenesis. Dysfunction is facilitated in part by the 7q11.23 protein DNAJC30, which interacts with mitochondrial ATP-synthase machinery. Removal of Dnajc30 in mice resulted in hypofunctional mitochondria, diminished morphological features of neocortical pyramidal neurons, and altered behaviors reminiscent of WS. The mitochondrial features are consistent with our observations of decreased integrity of oxidative phosphorylation supercomplexes and ATP-synthase dimers in WS. Thus, we identify DNAJC30 as an auxiliary component of ATP-synthase machinery and reveal mitochondrial maladies as underlying certain defects in brain development and function associated with WS. more...

To test the feasibility of using the SPICE (SPectroscopic Imaging by exploiting spatiospectral CorrElation) technique, which uses the partial separability of spectroscopic data, for high resolution hyperpolarized (HP)Numerical simulations were performed to investigate the impact of transient HP signals on SPICE reconstruction. Furthermore, spectroscopic imaging exams from SPICE and conventional EPSI (echo-planar spectroscopic imaging) were simulated for comparison. For in vivo experiments, HPThe variation of lactate/pyruvate from the simulated SPICE was less than 4% under various factors that affect the transient HP signal, suggesting that the impact is negligible. We found that while HPThe feasibility of HP more...

The phosphorylation state of heptapeptide repeats within the C-terminal domain (CTD) of the largest subunit of RNA Polymerase II (PolII) controls the transcription cycle and is maintained by the competing action of kinases and phosphatases. Rtr1 was recently proposed to be the enzyme responsible for the transition of PolII into the elongation and termination phases of transcription by removing the phosphate marker on Serine 5, but this attribution was questioned by the apparent lack of enzymatic activity. Here we demonstrate that Rtr1 is a phosphatase of new structure that is auto-inhibited by its own C-terminus. The enzymatic activity of the protein in vitro is functionally important in vivo as well: a single amino acid mutation that reduces activity leads to the same phenotype in vivo as deletion of the protein-coding gene from yeast. Surprisingly, Rtr1 dephosphorylates not only Serine 5 on the CTD, but also the newly described anti-termination Tyrosine 1 marker, supporting the hypothesis that Rtr1 and its homologs promote the transition from transcription to termination. more...

This study was conducted to evaluate the efficacy of two different formulations and application timings of benzobicyclon+penoxsulam+pyrzaosulfuron-ethyl (BPP) in rice field. BPP granule (GR) and tablet (TB) controlled more than 90% of four weed species 10 and 15 days after sowing in direct seeding when compared with untreated control. BPP TB was highly effective to control herbicide resistant Scirpus juncoides and Monochoria vaginalis both 10 and 15 days after transplanting (DAT). BPP GR controlled 94.0 and 96.5% of S. juncoides and M. vaginalis, respectively 10 DAT, but its efficacy decreased to 88.5 and 49.8% respectively 15 DAT. When compared with untreated control, no visual injuries were detected at 255 and 510 g a.i./ha of BPP. The yield of rice increased in both BPP GR and TB in transplanting and direct seeding rice cultivation when compared with untreated control. Based on these data, early application (10 DAT) of BPP GR and TB can be applied to provide effective weed control, especially in the field infested with herbicide resistant weed species. more...

To optimize and investigate the influence of bipolar gradients for flow suppression in metabolic quantification of hyperpolarizedThe trade-off between the amount of flow suppression using bipolar gradients and T2* effect from static spins was simulated. A free induction decay CSI sequence with alternations between the flow-suppressed and non-flow-suppressed acquisitions for each repetition time was developed and was applied to liver tumor-bearing mice via injection of hyperpolarized [1-The in vivo results from flow suppression using the velocity-optimized bipolar gradient were comparable with the simulation results. The vascular signal was adequately suppressed and signal loss in stationary tissue was minimized. Application of the velocity-optimized bipolar gradient to tumor-bearing mice showed reduction in the vessel-derived pyruvate signal contamination, and the average lactate/pyruvate ratio increased by 0.095 (P 0.05) in the tumor region after flow suppression.Optimization of the bipolar gradient is essential because of the short more...

Sulfonylurea herbicide-resistant weeds are spreading widely and distributed about 106,951 hectare in paddy rice fields in Korea. Morever all biotype of Scirpus juncoides which were collected at 69 spots all over paddy rice fields in 2008 were identified biotype of sulfonylurea herbicide-resistant. Benzobicyclon is a p-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor, which is absorbed through root and basal stem of weeds so cause bleaching of newly developing leaves. Benzobicyclon was very effective to control Scirpus juncoides, Monochoria vaginalis, sedges and broadleaves weeds, so it have been developed various formulation like a suspension concentrate (SC), a water dispersible granule (WG), a granule (GR) and a DT (tablet for Direct application). During recently 6 years, benzobicyclon-mixtures herbicides have been registered over than 54 products in paddy fields. Herbicidal efficacy by formulations of benzobicyclon and its mixture herbicides were highest in DT, followed by SC and GR. Herbicidal efficacy of the kaolin and carrier of GR was better and stable than that of talc and bentonite carrier. Growth and yield of rice were not affected much by formulations, application rates and rice cultivation methods. more...

The nanoporous F:SnO 2 materials prepared for the purpose of dye-sensitized solar cells (DSCs) application are composed of SnCl 4 (98.0%) and HF (48–51%), produce with a NH 4 OH aqueous solution with sol–gel method as a catalyst. Acetylene black is needed to make nano-porous from FTO heated until 120 °C that will change it from sol to gel and with that 2 phase sintering with 500 °C and 550 °C can be predicted to produce nano-materials. The preferred orientation indicates (110), (101), (211) for SnO 2 and (200) for fluorine, respectively. The main IR features include resonances at 660, 620 and 540 cm − 1 . From the FE-SEM results, the mean pore size of the sample is range of 16–38 nm. Finally, the nanoporous F:SnO 2 film used for TCO layer of dye-sensitized solar cells (DSCs) exhibited an energy conversion efficiency of about 1.83% at light intensity of 100 mW/cm 2 . more...

Titanium dioxide (TiO2) films were deposited on fluorine-doped tin-oxide (FTO) glass by sputtering and sol–gel combustion (SGC) coating methods and investigated with respect to their electrochemical luminescence (ECL) performance. The sputtered TiO2 films were denser than the SGC-deposited films, while the SGC films were found to be superior in porosity to the sputtered films. The charge transfer resistance (R 2) of the SGC (450 °C) TiO2-based cell was found to be lower than those of the sputtered TiO2-based cells. The SGC (450 °C) cell emitted a more intense ECL than the sputter (450 °C) cells. The threshold voltage at which the emission starts was 3.0 V for the SGC (450 °C) cell, which was lower than that (3.5 V) for the sputter (450 °C) cell. The efficiencies were 0.04 lm/W for the sputter (450 °C) cell (R 2 = 22.3 Ω, porosity= 27.2%) and 0.085 lm/W for the SGC (450 °C) cell (R 2 = 12.8 Ω, porosity= 65.8%). The SGC-deposited TiO2 films were found to be superior in ECL efficiency to the sputtered TiO2 films. more...