Bach1 gene ablation reduces steatohepatitis in mouse MCD diet model

Bach1 is a transcriptional repressor of heme oxygenase-1 (HO-1, a.k.a. HSP-32), which is an inducible enzyme and has anti-oxidation/anti-inflammatory properties shown in various models of organ injuries. Since oxidative stress plays a pivotal role in the pathogenesis of nonalcoholic steatohepatitis (NASH), HO-1 induction would be expected to prevent the development of NASH. In this study, we investigated the influence of Bach1 ablation in mice on the progression of NASH in methionine-choline deficient (MCD) diet model. Bach1 ablation resulted in significant induction of HO-1 mRNA and its activity in the liver. When fed MCD diet, Bach1−/− mice exhibited negligible hepatic steatosis compared to pronounced steatohepatitis in wild type mice with 6-fold increase in hepatic triglyceride content. Whereas feeding of MCD diet decreased mRNA expressions of peroxisome proliferator-activated receptor (PPAR) α and microsomal triglyceride transfer protein (MTP) in wild type mice, there were no change in Bach1−/− mice. In addition, hepatic concentration of malondialdehyde (MDA), a biomarker for oxidative stress as well as plasma alanine aminotransferase (ALT) was significantly lower in Bach1−/− mice. These findings suggest that Bach1 ablation exerts hepatoprotective effect against steatohepatitis presumably via HO-1 induction and may be a potential therapeutic target

Evaluating the malignant potential of intraductal papillary mucinous neoplasms of the pancreas : added value of non-enhanced endoscopic ultrasound to supplement non-enhanced magnetic resonance imaging

Purpose: To evaluate the diagnostic performance of combining non-enhanced magnetic resonance imaging (MRI) and non-enhanced endoscopic ultrasonography (EUS) for assessing the malignant potential of lesions in patients with intraductal papillary mucinous neoplasms of the pancreas (IPMNs). Material and methods: Data from 38 patients histopathologically diagnosed with IPMN adenomas or IPMN adenocarcinomas were retrospectively analysed. Preliminary univariate and multivariate analyses were conducted to identify statistically significant associations. Three blinded radiologists evaluated the image sets to assess the diagnostic performance of combined use of non-enhanced MRI and EUS as opposed to non-enhanced MRI alone in distinguishing malignant from benign lesions. Observer performance and interobserver variability were determined using receiver-operating-characteristic curve analysis and weighted κ statistics. Results: Multivariate analyses identified a significant difference between the abrupt change in the main pancreatic duct (MPD) calibre with distal pancreatic atrophy and the signal intensity of lesion-to-spinal cord ratio on MRI; a significant difference was observed in MPD size on EUS. Diagnostic performance assessments of the image sets did not differ significantly between the blinded radiologists. Conclusions: The clinical utility of non-enhanced EUS may be attributive in evaluating IPMN that has already been evaluated by non-enhanced MRI

Connective Tissue Growth Factor Gene Expression in Tissue Sections From Localized Scleroderma, Keloid, and Other Fibrotic Skin Disorders

Connective tissue growth factor (CTGF) is a novel peptide that exhibits platelet-derived growth factor-like activities and is produced by skin fibroblasts after activation with transforming growth factor-β. Coordinate expression of transforming growth factor-β followed by CTGF during wound repair suggests a cascade process for control of tissue regeneration. We recently reported a significant correlation between CTGF mRNA expression and histologic sclerosis in systemic sclerosis. To confirm the relation between CTGF and skin fibrosis, we investigated CTGF gene expression in tissue sections from patients with localized scleroderma, keloid, and other sclerotic skin disorders using nonradioactive in situ hybridization. In localized scleroderma, the fibroblasts with positive signals for CTGF mRNA were scattered throughout the sclerotic lesions with no preferential distribution around the inflammatory cells or perivascular regions, whereas the adjacent nonaffected dermis was negative for CTGF mRNA. In keloid tissue, the fibroblasts positive for CTGF mRNA were diffusely distributed, especially in the peripheral expanding lesions. In scar tissue, however, the fibroblasts in the fibrotic lesions showed partially positive signals for CTGF mRNA. In eosinophilic fasciitis, nodular fasciitis, and Dupuytren's contracture, CTGF mRNA was also expressed partially in the fibroblasts of the fibrotic lesions. Our findings reinforce a correlation between CTGF gene expression and skin sclerosis and support the hypothesis that transforming growth factor-β plays an important role in the pathogenesis of fibrosis, as it is the only inducer for CTGF identified to date

First determination of Pu isotopes (239Pu, 240Pu and 241Pu) in radioactive particles derived from Fukushima Daiichi Nuclear Power Plant accident

Radioactive particles were released into the environment during the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident. Many studies have been conducted to elucidate the chemical composition of released radioactive particles in order to understand their formation process. However, whether radioactive particles contain nuclear fuel radionuclides remains to be investigated. Here, we report the first determination of Pu isotopes in radioactive particles. To determine the Pu isotopes (239Pu, 240Pu and 241Pu) in radioactive particles derived from the FDNPP accident which were free from the influence of global fallout, radiochemical analysis and inductively coupled plasma-mass spectrometry measurements were conducted. Radioactive particles derived from unit 1 and unit 2 or 3 were analyzed. For the radioactive particles derived from unit 1, activities of 239+240Pu and 241Pu were (1.70-7.06)×10-5 Bq and (4.10-8.10)×10-3 Bq, respectively and atom ratios of 240Pu/239Pu and 241Pu/239Pu were 0.330-0.415 and 0.162-0.178, respectively. These ratios were consistent with the simulation results from ORIGEN code and measurements from various environmental samples. In contrast, Pu was not detected in the radioactive particles derived from unit 2 or 3. The difference in Pu contents is clear evidence towards different formation processes of radioactive particles, and detailed formation processes can be investigated from Pu analysis

Atmospheric resuspension of insoluble radioactive cesium-bearing particles found in the difficult-to-return area in Fukushima

The deposition of insoluble radiocesium-bearing microparticles (CsMPs), which were released from the Fukushima Daiichi Nuclear Power Plant (F1NPP) accident in March 2011, has resulted in the widespread contamination of eastern Japan. Obviously, these deposited insoluble CsMPs may become the secondary contamination sources by atmospheric migration or other environmental transferring process; however, the understanding of the transport mechanism remains non-elucidation, and the relevant evidence has not been directly provided. This study, for the first time, provides the direct evidence for the resuspension of these insoluble CsMPs to the atmosphere from (1) proximity of ¹³⁷Cs radioactivity and resemblance of the morphology and the elemental compositions of CsMPs in the samples of soil and aerosol derived from the same sampling site, (2) the special characteristics of the resuspended CsMPs of which the ratios of Na/Si, K/Si and/or Cs/Si were smaller than those from the initially released CsMPs collected at either long distance or near F1NPP, which can be ascribed to the slowly natural corrosion of CsMPs by the loss of the small amount of soluble contents in CsMPs, and (3) high CsMPs concentration of 10 granules/g in the surface soil of our sampling site and high resuspension frequency of CsMPs in spring when predominant suspended particles were soil dust. Specifically, 15 single CsMPs were successfully isolated from the aerosol filters collected by unmanned high-volume air samplers at a severely polluted area in Fukushima Prefecture, about 25 km away from F1NPP, from January 2015 to September 2019. The mean diameter of these CsMPs was 1.8 ± 0.5 μm, and the average ¹³⁷Cs radioactivity was 0.35 ± 0.23 Bq/granule. The contribution rate of the resuspended CsMPs to the atmospheric radiocesium was estimated from the ratio of ¹³⁷Cs radioactivity of a single CsMP to that of the aerosol filter to be of 23.9 ± 15.3%. There has been no considerable decreasing trend in the annual CsMP resuspension frequency

Actin Family in INO80 Complex

Nuclear actin family proteins, comprising of actin and actin-related proteins (Arps), are essential functional components of the multiple chromatin remodeling complexes. The INO80 chromatin remodeling complex, which is evolutionarily conserved and has roles in transcription, DNA replication and repair, consists of actin and actin-related proteins Arp4, Arp5, and Arp8. We generated Arp5 knockout (KO) and Arp8 KO cells from the human Nalm-6 pre-B cell line and used these KO cells to examine the roles of Arp5 and Arp8 in the transcriptional regulation mediated by the INO80 complex. In both of Arp5 KO and Arp8 KO cells, the oxidative stress-induced expression of HMOX1 gene, encoding for heme oxygenase-1 (HO-1), was significantly impaired. Consistent with these observations, chromatin immunoprecipitation (ChIP) assay revealed that oxidative stress caused an increase in the binding of the INO80 complex to the regulatory sites of HMOX1 in wild-type cells. The binding of INO80 complex to chromatin was reduced in Arp8 KO cells compared to that in the wild-type cells. On the other hand, the binding of INO80 complex to chromatin in Arp5 KO cells was similar to that in the wild-type cells even under the oxidative stress condition. However, both remodeling of chromatin at the HMOX1 regulatory sites and binding of a transcriptional activator to these sites were impaired in Arp5 KO cells, indicating that Arp5 is required for the activation of the INO80 complex. Collectively, these results suggested that these nuclear Arps play indispensable roles in the function of the INO80 chromatin remodeling complex

Distinctive nuclear zone for RAD51-mediated homologous recombinational DNA repair

Genome-based functions are inseparable from the dynamic higher-order architecture of the cell nucleus. In this context, the repair of DNA damage is coordinated by precise spatiotemporal controls that target and regulate the repair machinery required to maintain genome integrity. However, the mechanisms that pair damaged DNA with intact template for repair by homologous recombination (HR) without illegitimate recombination remain unclear. This report highlights the intimate relationship between nuclear architecture and HR in mammalian cells. RAD51, the key recombinase of HR, forms spherical foci in S/G2 phases spontaneously. Using super-resolution microscopy, we show that following induction of DNA double-strand breaks RAD51 foci at damaged sites elongate to bridge between intact and damaged sister chromatids; this assembly occurs within bundle-shaped distinctive nuclear zones, requires interactions of RAD51 with various factors, and precedes ATP-dependent events involved the recombination of intact and damaged DNA. We observed a time-dependent transfer of single-stranded DNA overhangs, generated during HR, into such zones. Our observations suggest that RAD51-mediated homologous pairing during HR takes place within the distinctive nuclear zones to execute appropriate recombination

The seasonal variations of atmospheric 134,137Cs activity and possible host particles for their resuspension in the contaminated areas of Tsushima and Yamakiya, Fukushima, Japan

A large quantity of radionuclides was released by the Fukushima Daiichi Nuclear Power Plant accident in March 2011, and those deposited on ground and vegetation could return to the atmosphere through resuspension processes. Although the resuspension has been proposed to occur with wind blow, biomass burning, ecosystem activities, etc., the dominant process in contaminated areas of Fukushima is not fully understood. We have examined the resuspension process of radiocesium (134,137Cs) based on long-term measurements of the atmospheric concentration of radiocesium activity (the radiocesium concentration) at four sites in the contaminated areas of Fukushima as well as the aerosol characteristic observations by scanning electron microscopy (SEM) and the measurement of the biomass burning tracer, levoglucosan.The radiocesium concentrations at all sites showed a similar seasonal variation: low from winter to early spring and high from late spring to early autumn. In late spring, they showed positive peaks that coincided with the wind speed peaks. However, in summer and autumn, they were correlated positively with atmospheric temperature but negatively with wind speed. These results differed from previous studies based on data at urban sites. The difference of radiocesium concentrations at two sites, which are located within a 1 km range but have different degrees of surface contamination, was large from winter to late spring and small in summer and autumn, indicating that resuspension occurs locally and/or that atmospheric radiocesium was not well mixed in winter/spring, and it was opposite in summer/autumn. These results suggest that the resuspension processes and the host particles of the radiocesium resuspension changed seasonally. The SEM analyses showed that the dominant coarse particles in summer and autumn were organic ones, such as pollen, spores, and microorganisms. Biological activities in forest ecosystems can contribute considerably to the radiocesium resuspension in these seasons. During winter and spring, soil, mineral, and vegetation debris were predominant coarse particles in the atmosphere, and the radiocesium resuspension in these seasons can be attributed to the wind blow of these particles. Any proofs that biomass burning had a significant impact on atmospheric radiocesium were not found in the present study