Statins Activate Human PPARα Promoter and Increase PPARα mRNA Expression and Activation in HepG2 Cells

Statins increase peroxisome proliferator-activated receptor α (PPARα) mRNA expression, but the mechanism of this increased PPARα production remains elusive. To examine the regulation of PPARα production, we examined the effect of 7 statins (atorvastatin, cerivastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) on human PPARα promoter activity, mRNA expression, nuclear protein levels, and transcriptional activity. The main results are as follows. (1) Majority of statins enhanced PPARα promoter activity in a dose-dependent manner in HepG2 cells transfected with the human PPARα promoter. This enhancement may be mediated by statin-induced HNF-4α. (2) PPARα mRNA expression was increased by statin treatment. (3) The PPARα levels in nuclear fractions were increased by statin treatment. (4) Simvastatin, pravastatin, and cerivastatin markedly enhanced transcriptional activity in 293T cells cotransfected with acyl-coenzyme A oxidase promoter and PPARα/RXRα expression vectors. In summary, these data demonstrate that PPARα production and activation are upregulated through the PPARα promoter activity by statin treatment

Reproducibility of Non-X-ray Background for the X-ray Imaging Spectrometer aboard Suzaku

One of the advantages of the X-ray Imaging Spectrometer (XIS) system on board Suzaku is its low and stable non-X-ray background (NXB). In order to make the best use of this advantage, modeling the NXB spectra with high accuracy is important to subtract them from the spectra of on-source observations. We construct an NXB database by collecting XIS events when the dark Earth covers the XIS FOV. The total exposure time of the NXB data is about 785 ks for each XIS. It is found that the count rate of the NXB anti-correlates with the cut-off-rigidity and correlates with the count rate of the PIN upper discriminator (PIN-UD) in Hard X-ray Detector on board Suzaku. We thus model the NXB spectrum for a given on-source observation by employing either of these parameters and obtain a better reproducibility of the NXB for the model with PIN-UD than that with the cut-off-rigidity. The reproducibility of the NXB model with PIN-UD is 4.55-5.63% for each XIS NXB in the 1-7 keV band and 2.79-4.36% for each XIS NXB in the 5-12 keV band for each 5 ks exposure of the NXB data. This NXB reproducibility is much smaller than the spatial fluctuation of the cosmic X-ray background in the 1-7 keV band, and is almost comparable to that in the 5-12 keV band.Comment: 25 pages, 13 figures, accepted for publication in PASJ (Suzaku Special Issue

An Al-doped SrTiO3 photocatalyst maintaining sunlight-driven overall water splitting activity for over 1000 h of constant illumination

Photocatalytic water splitting is a viable approach to the large-scale production of renewable solar hydrogen. The apparent quantum yield for this reaction has been improved, but the lifespan of photocatalysts functioning under sunlight at ambient pressure have rarely been examined, despite the critical importance of this factor in practical applications. Herein, we show that Al-doped SrTiO3 (SrTiO3: Al) loaded with a RhCrOx (rhodium chromium oxide) cocatalyst splits water with an apparent quantum yield greater than 50% at 365 nm. Moreover, following the photodeposition of CoOOH and TiO2, this material maintains 80% of its initial activity and a solar-to-hydrogen energy conversion efficiency greater than or equal to 0.3% over a span of 1300 h under constant illumination by simulated sunlight at ambient pressure. This result is attributed to reduced dissolution of Cr in the cocatalyst following the oxidative photodeposition of CoOOH. The photodeposition of TiO2 further improves the durability of this photocatalyst. This work demonstrates a concept that could allow the design of longterm, large-scale photocatalyst systems for practical sunlight-driven water splitting.ArticleCHEMICAL SCIENCE.10(11):3196-3201(2019)journal articl

LRRN4 and UPK3B Are Markers of Primary Mesothelial Cells

Mesothelioma is a highly malignant tumor that is primarily caused by occupational or environmental exposure to asbestos fibers. Despite worldwide restrictions on asbestos usage, further cases are expected as diagnosis is typically 20–40 years after exposure. Once diagnosed there is a very poor prognosis with a median survival rate of 9 months. Considering this the development of early pre clinical diagnostic markers may help improve clinical outcomes.Microarray expression arrays on mesothelium and other tissues dissected from mice were used to identify candidate mesothelial lineage markers. Candidates were further tested by qRTPCR and in-situ hybridization across a mouse tissue panel. Two candidate biomarkers with the potential for secretion, uroplakin 3B (UPK3B), and leucine rich repeat neuronal 4 (LRRN4) and one commercialized mesothelioma marker, mesothelin (MSLN) were then chosen for validation across a panel of normal human primary cells, 16 established mesothelioma cell lines, 10 lung cancer lines, and a further set of 8 unrelated cancer cell lines.Within the primary cell panel, LRRN4 was only detected in primary mesothelial cells, but MSLN and UPK3B were also detected in other cell types. MSLN was detected in bronchial epithelial cells and alveolar epithelial cells and UPK3B was detected in retinal pigment epithelial cells and urothelial cells. Testing the cell line panel, MSLN was detected in 15 of the 16 mesothelioma cells lines, whereas LRRN4 was only detected in 8 and UPK3B in 6. Interestingly MSLN levels appear to be upregulated in the mesothelioma lines compared to the primary mesothelial cells, while LRRN4 and UPK3B, are either lost or down-regulated. Despite the higher fraction of mesothelioma lines positive for MSLN, it was also detected at high levels in 2 lung cancer lines and 3 other unrelated cancer lines derived from papillotubular adenocarcinoma, signet ring carcinoma and transitional cell carcinoma

Synthesis of [11C]uric acid, using [11C]phosgene, as a possible biomarker in PET imaging for diagnosis of gout

The synthesis and in vivo evaluation of 11C -labeled uric acid ([11C]1), a potential imaging agent for the diagnosis of urate-related life-style diseases, was performed using positron emission tomography (PET) image analysis. First, the synthesis of [11C]1 was achieved by reacting 5,6-diaminouracil (2) with 11C-labeled phosgene ([11C]COCl2). The radiochemical yield of [11C]1 was 37 ± 7% (decay-corrected based on [11C]COCl2) with specific radioactivities of 96-152 GBq/μmol at the end of synthesis (n = 6). The average time of radiosynthesis from the end of bombardment, including formulation, was about 30 min with >98% radiochemical purity. Second, the synthetic approach to [11C]1 was optimized using 5,6-diaminouracil sulfate (3) with [11C]COCl2 in the presence of 1,8-bis(dimethylamino)naphthalene. [11C]1 was synthesized in 36 ± 6% radiochemical yield, 89-142 GBq/μmol of specific radioactivities, and 98% radiochemical purity by this method (n = 5). This allowed the synthesis of [11C]1 to be carried out repeatedly and the radiochemical yield, specific radioactivities, average time of synthesis, and radiochemical purity of [11C]1 were similar to those obtained using 2. PET studies in rats showed large differences in the accumulation of radioligand in the limbs under normal and hyperuricemic conditions. Thus, an efficient and convenient automated synthesis of [11C]1 has been developed, and preliminary PET evaluation of [11C]1 confirmed the increased accumulation of radioactivity in the limbs of a rat model of hyperuricemia. © 2011 Elsevier Ltd. All rights reserved

COL4A6 is dispensable for autosomal recessive Alport syndrome

Alport syndrome is caused by mutations in the genes encoding alpha 3, alpha 4, or alpha 5 (IV) chains. Unlike X-linked Alport mice, alpha 5 and alpha 6 (IV) chains are detected in the glomerular basement membrane of autosomal recessive Alport mice, however, the significance of this finding remains to be investigated. We therefore generated mice lacking both alpha 3 and alpha 6 (IV) chains and compared their renal function and survival with Col4a3 knockout mice of 129 x 1/Sv background. No significant difference was observed in the renal function or survival of the two groups, or when the mice were backcrossed once to C57BL/6 background. However, the survival of backcrossed double knockout mice was significantly longer than that of the mice of 129 x 1/Sv background, which suggests that other modifier genes were involved in this phenomenon. In further studies we identified two Alport patients who had a homozygous mutation in intron 46 of COL4A4. The alpha 5 and alpha 6 (IV) chains were focally detected in the glomerular basement membrane of these patients. These findings indicate that although a5 and a6 (IV) chains are induced in the glomerular basement membrane in autosomal recessive Alport syndrome, their induction does not seem to play a major compensatory role.Peer reviewe

Transcript Annotation in FANTOM3: Mouse Gene Catalog Based on Physical cDNAs

The international FANTOM consortium aims to produce a comprehensive picture of the mammalian transcriptome, based upon an extensive cDNA collection and functional annotation of full-length enriched cDNAs. The previous dataset, FANTOM2, comprised 60,770 full-length enriched cDNAs. Functional annotation revealed that this cDNA dataset contained only about half of the estimated number of mouse protein-coding genes, indicating that a number of cDNAs still remained to be collected and identified. To pursue the complete gene catalog that covers all predicted mouse genes, cloning and sequencing of full-length enriched cDNAs has been continued since FANTOM2. In FANTOM3, 42,031 newly isolated cDNAs were subjected to functional annotation, and the annotation of 4,347 FANTOM2 cDNAs was updated. To accomplish accurate functional annotation, we improved our automated annotation pipeline by introducing new coding sequence prediction programs and developed a Web-based annotation interface for simplifying the annotation procedures to reduce manual annotation errors. Automated coding sequence and function prediction was followed with manual curation and review by expert curators. A total of 102,801 full-length enriched mouse cDNAs were annotated. Out of 102,801 transcripts, 56,722 were functionally annotated as protein coding (including partial or truncated transcripts), providing to our knowledge the greatest current coverage of the mouse proteome by full-length cDNAs. The total number of distinct non-protein-coding transcripts increased to 34,030. The FANTOM3 annotation system, consisting of automated computational prediction, manual curation, and final expert curation, facilitated the comprehensive characterization of the mouse transcriptome, and could be applied to the transcriptomes of other species

An In Vitro Model for Lewy Body-Like Hyaline Inclusion/Astrocytic Hyaline Inclusion: Induction by ER Stress with an ALS-Linked SOD1 Mutation

Neuronal Lewy body-like hyaline inclusions (LBHI) and astrocytic hyaline inclusions (Ast-HI) containing mutant Cu/Zn superoxide dismutase 1 (SOD1) are morphological hallmarks of familial amyotrophic lateral sclerosis (FALS) associated with mutant SOD1. However, the mechanisms by which mutant SOD1 contributes to formation of LBHI/Ast-HI in FALS remain poorly defined. Here, we report induction of LBHI/Ast-HI-like hyaline inclusions (LHIs) in vitro by ER stress in neuroblastoma cells. These LHI closely resemble LBHI/Ast-HI in patients with SOD1-linked FALS. LHI and LBHI/Ast-HI share the following features: 1) eosinophilic staining with a pale core, 2) SOD1, ubiquitin and ER resident protein (KDEL) positivity and 3) the presence of approximately 15–25 nm granule-coated fibrils, which are morphological hallmark of mutant SOD1-linked FALS. Moreover, in spinal cord neurons of L84V SOD1 transgenic mice at presymptomatic stage, we observed aberrant aggregation of ER and numerous free ribosomes associated with abnormal inclusion-like structures, presumably early stage neuronal LBHI. We conclude that the LBHI/Ast-HI seen in human patients with mutant SOD1-linked FALS may arise from ER dysfunction

Review Article : Feudalism or Absolute Monarchism?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68809/2/10.1177_009770049001600304.pd

Fundamental physics activities with pulsed neutron at J-PARC(BL05)

"Neutron Optics and Physics (NOP/ BL05)" at MLF in J-PARC is a beamline for studies of fundamental physics. The beamline is divided into three branches so that different experiments can be performed in parallel. These beam branches are being used to develop a variety of new projects. We are developing an experimental project to measure the neutron lifetime with total uncertainty of 1 s (0.1%). The neutron lifetime is an important parameter in elementary particle and astrophysics. Thus far, the neutron lifetime has been measured by several groups; however, different values are obtained from different measurement methods. This experiment is using a method with different sources of systematic uncertainty than measurements conducted to date. We are also developing a source of pulsed ultra-cold neutrons (UCNs) produced from a Doppler shifter are available at the unpolarized beam branch. We are developing a time focusing device for UCNs, a so called "rebuncher", which can increase UCN density from a pulsed UCN source. At the low divergence beam branch, an experiment to search an unknown intermediate force with nanometer range is performed by measuring the angular dependence of neutron scattering by noble gases. Finally the beamline is also used for the research and development of optical elements and detectors. For example, a position sensitive neutron detector that uses emulsion to achieve sub-micrometer resolution is currently under development. We have succeeded in detecting cold and ultra-cold neutrons using the emulsion detector.Comment: 9 pages, 5 figures, Proceedings of International Conference on Neutron Optics (NOP2017