Overexpression of Nuclear Receptor 5A1 Induces and Maintains an Intermediate State of Conversion between Primed and Naive Pluripotency

Naive and primed human pluripotent stem cells (hPSCs) have provided useful insights into the regulation of pluripotency. However, the molecular mechanisms regulating naive conversion remain elusive. Here, we report intermediate naive conversion induced by overexpressing nuclear receptor 5A1 (NR5A1) in hPSCs. The cells displayed some naive features, such as clonogenicity, glycogen synthase kinase 3β, and mitogen-activated protein kinase (MAPK) independence, expression of naive-associated genes, and two activated X chromosomes, but lacked others, such as KLF17 expression, transforming growth factor β independence, and imprinted gene demethylation. Notably, NR5A1 negated MAPK activation by fibroblast growth factor 2, leading to cell-autonomous self-renewal independent of MAPK inhibition. These phenotypes may be associated with naive conversion, and were regulated by a DPPA2/4-dependent pathway that activates the selective expression of naive-associated genes. This study increases our understanding of the mechanisms regulating the conversion from primed to naive pluripotency

Grading Meningioma : A Comparative Study of Thallium-SPECT and FDG-PET

The purpose was to compare capability of fluorine-18 fluorodeoxyglucose (FDG)-PET and thallium-201 (Tl)-SPECT for grading meningioma. This retrospective study was conducted as a case-control study under approval by the institutional review board. In the hospital information system, 67 patients (22 men and 45 women) who had both FDG-PET and Tl-SPECT preoperative examinations were found with histopathologic diagnosis of meningioma. The maximum FDG uptake values of the tumors were measured, and they were standardized to the whole body (SUVmax) and normalized as gray matter ratio (SUVRmax). Mean and maximum Tl uptake ratios (TURmean and TURmax, respectively) of the tumors were measured and normalized as ratios to those of the contralateral normal brain. Receiver-operating characteristic curve analyses of the 4 indexes were conducted for differentiation between low- and high-grade meningiomas, and areas under the curves (AUCs) were compared. Correlation coefficients were calculated between these indexes and Ki-67. Fifty-six meningiomas were classified as grade I (low grade), and 11 were grade II or III (high grade). In all 4 indexes, a significant difference was observed between low- and high-grade meningiomas (P<0.05). AUCs were 0.817 (SUVmax), 0.781 (SUVRmax), 0.810 (TURmean), and 0.831 (TURmax), and no significant difference was observed among the indexes. Their sensitivity and specificity were 72.7% to 90.9% and 71.4% to 87.5%, respectively. Correlation of the 4 indexes to Ki-67 was statistically significant, but coefficients were relatively low (0.273-0.355). Tl-SPECT, which can be used at hospitals without a cyclotron or an FDG distribution network, has high diagnostic capability of meningioma grades comparable to FDG-PET

Spectral evolution of GRB 060904A observed with Swift and Suzaku -- Possibility of Inefficient Electron Acceleration

We observed an X-ray afterglow of GRB 060904A with the Swift and Suzaku satellites. We found rapid spectral softening during both the prompt tail phase and the decline phase of an X-ray flare in the BAT and XRT data. The observed spectra were fit by power-law photon indices which rapidly changed from $\Gamma = 1.51^{+0.04}_{-0.03}$ to $\Gamma = 5.30^{+0.69}_{-0.59}$ within a few hundred seconds in the prompt tail. This is one of the steepest X-ray spectra ever observed, making it quite difficult to explain by simple electron acceleration and synchrotron radiation. Then, we applied an alternative spectral fitting using a broken power-law with exponential cutoff (BPEC) model. It is valid to consider the situation that the cutoff energy is equivalent to the synchrotron frequency of the maximum energy electrons in their energy distribution. Since the spectral cutoff appears in the soft X-ray band, we conclude the electron acceleration has been inefficient in the internal shocks of GRB 060904A. These cutoff spectra suddenly disappeared at the transition time from the prompt tail phase to the shallow decay one. After that, typical afterglow spectra with the photon indices of 2.0 are continuously and preciously monitored by both XRT and Suzaku/XIS up to 1 day since the burst trigger time. We could successfully trace the temporal history of two characteristic break energies (peak energy and cutoff energy) and they show the time dependence of $\propto t^{-3} \sim t^{-4}$ while the following afterglow spectra are quite stable. This fact indicates that the emitting material of prompt tail is due to completely different dynamics from the shallow decay component. Therefore we conclude the emission sites of two distinct phenomena obviously differ from each other.Comment: 19 pages, 9 figures, accepted for publication in PASJ (Suzaku 2nd Special Issue

Anti-inflammatory Effect of Ghrelin in Lymphoblastoid Cell Lines From Children With Autism Spectrum Disorder

The gut hormone ghrelin has been implicated in a variety of functional roles in the central nervous system through the brain-gut axis, one of which is an anti-inflammatory effect. An aberrant brain-gut axis producing immune dysfunction has been implicated in the pathobiology of autism spectrum disorder (ASD), and elevated expression of inflammatory markers has been shown in blood and brain tissue from subjects with ASD. We hypothesized that ghrelin may mitigate this effect. Lymphoblastoid cell lines from typically developed children (TD-C) (N = 20) and children with ASD (ASD-C) (N = 20) were cultured with PBS or human ghrelin (0.01 μM) for 24 h, and mRNA expression levels of the inflammation-related molecules interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and nuclear factor kappa B (NF-κB) were measured to examine the effects of ghrelin as an anti-inflammatory agent. Expression levels of TNF-α and NF-κB mRNA, but not IL-1β or IL-6, were significantly elevated in ASD-C compared to TD-C. Ghrelin showed a tendency to reduce the expression of TNF-α and NF-κB, but this was not statistically significant. Considering the heterogenous pathobiology of ASD, we examined the effects of ghrelin on TD-C and ASD-C with expression levels of TNF-α and NF-κB in the highest and lowest quartiles. We found that ghrelin markedly reduced mRNA expression of TNF-α and NF-κB s in ASD-C with highest-quartile expression, but there were no effects in ASD-C with lowest-quartile expression, TD-C with highest quartile expression, or TD-C with lowest quartile expression. Together, these findings suggest that ghrelin has potential as a novel therapeutic agent for ASD with inflammation and/or immune dysfunction

アルドステロン分泌に及ぼす血液pHの影響について

The present investigation was carried out to elucidate whether changes in blood pH induced by administrations of alkalinizing or acidifing agents influence aldosterone secretion. Since aldosterone secretion is known to be regulated by various factors such as the renin-angiotensin system, adrenocorticotropin (ACTH) and serum potassium level, these indices were simultaneously measured during manipulation. Oral administration of NaHCO_3 (alkalinization) of 0.3g・body weight^ resulted in a fall of serum aldosterone with an increase in blood pH, whereas serum cortisol and plasma renin activity remained unchanged. NH_4Cl ingestion (acidification) caused an elevation of aldosterone though the increase was not significant statistically, whereas CaCO_3 ingestion (control) resulted in a significant fall in serum aldosterone. In the experiment of NH_4Cl ingestion, both serum cortisol and plasma renin activity decreased significantly. These results suggest that the fall of aldosterone by alkalinization and the rise of aldosterone by acidification are not induced by either renin angiotensin system or ACTH. On the other hand, serum potassium level fell or rose during alkalinization or acidification. The pattern of the change was similar to the change in proton concentration. From these results, it is concluded that changes in blood pH seem to influence aldosterone secretion independent of renin angiotensin system and ACTH, however, possible involvement of serum potassium concentration on aldosterone secretion can not be denied

Transcriptional Regulation of an Evolutionary Conserved Intergenic Region of CDT2-INTS7

In the mammalian genome, a substantial number of gene pairs (approximately 10%) are arranged head-to-head on opposite strands within 1,000 base pairs, and separated by a bidirectional promoter(s) that generally drives the co-expression of both genes and results in functional coupling. The significance of unique genomic configuration remains elusive.Here we report on the identification of an intergenic region of non-homologous genes, CDT2, a regulator of DNA replication, and an integrator complex subunit 7 (INTS7), an interactor of the largest subunit of RNA polymerase II. The CDT2-INTS7 intergenic region is 246 and 245 base pairs long in human and mouse respectively and is evolutionary well-conserved among several mammalian species. By measuring the luciferase activity in A549 cells, the intergenic human sequence was shown to be able to drive the reporter gene expression in either direction and notably, among transcription factors E2F, E2F1 approximately E2F4, but not E2F5 and E2F6, this sequence clearly up-regulated the reporter gene expression exclusively in the direction of the CDT2 gene. In contrast, B-Myb, c-Myb, and p53 down-regulated the reporter gene expression in the transcriptional direction of the INTS7 gene. Overexpression of E2F1 by adenoviral-mediated gene transfer resulted in an increased CDT2, but not INTS7, mRNA level. Real-time polymerase transcription (RT-PCR) analyses of the expression pattern for CDT2 and INTS7 mRNA in human adult and fetal tissues and cell lines revealed that transcription of these two genes are asymmetrically regulated. Moreover, the abundance of mRNA between mouse and rat tissues was similar, but these patterns were quite different from the results obtained from human tissues.These findings add a unique example and help to understand the mechanistic insights into the regulation of gene expression through an evolutionary conserved intergenic region of the mammalian genome

Optimization of prediction methods for risk assessment of pathogenic germline variants in the Japanese population

Predicting pathogenic germline variants (PGVs) in breast cancer patients is important for selecting optimal therapeutics and implementing risk reduction strategies. However, PGV risk factors and the performance of prediction methods in the Japanese population remain unclear. We investigated clinicopathological risk factors using the Tyrer-Cuzick (TC) breast cancer risk evaluation tool to predict BRCA PGVs in unselected Japanese breast cancer patients (n = 1, 995). Eleven breast cancer susceptibility genes were analyzed using target-capture sequencing in a previous study; the PGV prevalence in BRCA1, BRCA2, and PALB2 was 0.75%, 3.1%, and 0.45%, respectively. Significant associations were found between the presence of BRCA PGVs and early disease onset, number of familial cancer cases (up to third-degree relatives), triple-negative breast cancer patients under the age of 60, and ovarian cancer history (all P < .0001). In total, 816 patients (40.9%) satisfied the National Comprehensive Cancer Network (NCCN) guidelines for recommending multigene testing. The sensitivity and specificity of the NCCN criteria for discriminating PGV carriers from noncarriers were 71.3% and 60.7%, respectively. The TC model showed good discrimination for predicting BRCA PGVs (area under the curve, 0.75; 95% confidence interval, 0.69-0.81). Furthermore, use of the TC model with an optimized cutoff of TC score ≥0.16% in addition to the NCCN guidelines improved the predictive efficiency for high-risk groups (sensitivity, 77.2%; specificity, 54.8%; about 11 genes). Given the influence of ethnic differences on prediction, we consider that further studies are warranted to elucidate the role of environmental and genetic factors for realizing precise prediction

Analysis of Achievement on Biology Test in Lao People\u27s Democratic Republic

We studied the 9th grade science achievements, focusing on Biology, of Lao students in Vientiane capital, Lao People\u27s Democratic Republic (Lao PDR, or Laos). Our survey-using selected questions on Biology from Trends in International Mathematics and Science Study (TIMSS) 2011-was conducted in February 2015 on a total of 388 9th grade students from 3 lower secondary schools (3 districts in Vientiane capital). We analyzed the average correctness of Lao students, and compared them with Japanese and average of all OECD countries. We found that a school with less ideal educational condition in the Outskirts Zone of the Vientiane Capital scored lower points comparing to the Urban schools. Also, it seems that science education in Laos focuses more on Reasoning skills than Knowledge or Application skills