Permeability of the fish intestinal membrane to bulky chemicals

The ability to predict the environmental behavior of chemicals precisely is important for realizing more rational regulation. In this study, the bioaccumulation of nine chemicals of different molecular weights absorbed via the intestinal tract was evaluated in fish using the everted gut sac method. The amounts of chemicals that passed through the intestinal membrane after a 24-hr exposure were significantly decreased for chemicals with MW≥548 and Dmax min≥15.8 Å (or Dmax aver≥17.2 Å). These thresholds are consistent with those previously proposed in terms of MW (>800) and molecular size (Dmax min>15.6 Å or Dmax aver>17.1 Å) for the limit of permeable chemicals through the gill membrane. The results show that the same MW and Dmax criteria can be used to predict low bioaccumulation through both the gill membrane and the intestinal tract. These findings are helpful in reducing the need to conduct animal tests in environmental safety studies

Criterion of molecular size to evaluate the bioaccumulation potential of chemicals in fish

To evaluate the bioaccumulation potential of chemicals in fish, a molecular-size descriptor, Dmax aver, has been used as a weight of evidence under the EU REACH. The Dmax aver value, however, is estimated on the basis of 3-D structures of possible stable conformers in a vacuum using OASIS software that requires expertise upon parameter input. We developed a method to calculate the 3-D conformers in water, which is more suitable for bioaccumulation potential evaluation in an aquatic environment, by introducing MD simulation. By examining the relationship of the calculated molecular size of 1665 chemicals with their reported BCF values, we found that 17.1 Å of Dmax aver or 15.6 Å of Dmax min was a threshold of molecular size in water to predict the low bioaccumulation (i.e., BCF<5000) of a chemical. Setting this threshold as a new standard would reduce the number of animal tests without compromising the quality of safety evaluation

Investigation of the feasibility of a simple method for verifying the motion of a binary multileaf collimator synchronized with the rotation of the gantry for helical tomotherapy

In this paper, we suggest a new method for verifying the motion of a binary multileaf collimator (MLC) in helical tomotherapy. For this we used a combination of a cylindrical scintillator and a general-purpose camcorder. The camcorder records the light from the scintillator following photon irradiation, which we use to track the motion of the binary MLC. The purpose of this study is to demonstrate the feasibility of this method as a binary MLC quality assurance (QA) tool. First, the verification was performed using a simple binary MLC pattern with a constant leaf open time; secondly, verification using the binary MLC pattern used in a clinical setting was also performed. Sinograms of simple binary MLC patterns, in which leaves that were open were detected as "open" from the measured light, define the sensitivity which, in this case, was 1.000. On the other hand, the specificity, which gives the fraction of closed leaves detected as "closed", was 0.919. The leaf open error identified by our method was -1.3 +/- 7.5%. The 68.6% of observed leaves were performed within +/- 3% relative error. The leaf open error was expressed by the relative errors calculated on the sinogram. In the clinical binary MLC pattern, the sensitivity and specificity were 0.994 and 0.997, respectively. The measurement could be performed with -3.4 +/- 8.0% leaf open error. The 77.5% of observed leaves were performed within +/- 3% relative error. With this method, we can easily verify the motion of the binary MLC, and the measurement unit developed was found to be an effective QA tool.ArticleJOURNAL OF APPLIED CLINICAL MEDICAL PHYSICS. 13(1):27-43 (2012)journal articl

Novel potential of tunicamycin as an activator of the aryl hydrocarbon receptor – dioxin responsive element signaling pathway

AbstractTunicamycin is a well-known inhibitor of protein glycosylation and used as an inducer of endoplasmic reticulum (ER) stress. We found that tunicamycin induced expression of cytochrome P450 1A1 in a dose-dependent manner. Like dioxin, the transcriptional induction was associated with dose-dependent activation of the dioxin responsive element (DRE). This effect was independent of inhibition of protein glycosylation or induction of ER stress. Pharmacological and genetic inhibition of the aryl hydrocarbon receptor (AhR) significantly attenuated activation of DRE by tunicamycin. These results elucidated the novel potential of tunicamycin as an activator of the AhR – DRE signaling pathway

A\u27\u27Translanguaging" developmental Assessment should be given to CLD children - A study to distinguish behveen a developmental disorder and temporary double-limited -

現在日本の小学校の特別支援学級には数多くの外国にルーツを持つ児童（CLO児童）が在籍している。CLO児童は一般的に一時的なダブルリミテッド状況にあるのか機能的障害なのかの見分けがつきにくく，特別支援学級に誤配躍されるケースが多く見られる。特に集住地区である東海地区においては，多くのブラジル国籍の児童が特別支援学級に在籍している。本研究では，日本の学校の特別支援学級に在籍，または発達障害と見られている日系ブラジル人児童6名に対し，ポルトガル語と日本語の言語能力調査と，ポルトガル語と日本語による知能検査(WISC-N)を行った。その結果，IQ, 行動観察共に障害がないと思われる児童が2名いた。また，CLO児童は言語相補的にパフォーマンスが現れる可能性があることが明らかになった。この結果よりバイリンガルテスターによる発達アセスメントを行う必要性があることが示唆された。In recent years, a special-needs class of elementary school in Japan enrolls many CLD children who have roots in foreign countries. Generally, it is difficult for a CLD child to tell whether it is temporary double-limited or functional obstacle, and many cases are misdirected in a special-needs class. Especially in the Tokai area, which many Brazilian live children are enrolled in those classes. In this study, six Japanese Brazilian children enrolled in a special needs class of Japanese elementary school or seen as a developmental disorder are asked to investigate the language ability of Portuguese and Japanese, intelligence test in Portuguese and Japanese (WISC-IV) was conducted. As a result, there were two children who seemed to have no obstacles with both IQ and behavioral observation. In addition, it became clear that there is a possibility that CLD children appear performance linguistically complementarily. As a result, it was suggested that there is a need to conduct a developmental assessment by a bilingual tester

CRL4VprBP E3 Ligase Promotes Monoubiquitylation and Chromatin Binding of TET Dioxygenases

DNA methylation at the C-5 position of cytosine (5mC) regulates gene expression and plays pivotal roles in various biological processes. The TET dioxygenases iterative oxidation of 5mC, leading to eventual demethylation intermediate. Inactivation of TET enzymes causes multi-stage developmental defects, impaired cell reprogramming and hematopoietic malignancies. However, little is known about how TET activity is regulated. Here we show that all three TET proteins bind to VprBP and are monoubiquitylated by the VprBP-DDB1-CUL4-ROC1 E3 ubiquitin ligase (CRL4VprBP) on a highly conserved lysine residue. Deletion of VprBP in oocytes abrogated paternal DNA hydroxymethylation in zygotes. VprBP-mediated monoubiquitylation promotes TET binding to chromatin. Multiple recurrent TET2-inactivating mutations derived from leukemia target either the monoubiquitylation site (K1299) or residues essential for VprBP binding. Cumulatively, our data demonstrate that CRL4VprBP is a critical regulator of TET dioxygenases during development and in tumor suppression

Safety and Efficacy of FIT039 for Verruca Vulgaris: A Placebo-Controlled, Phase I/II Randomized Controlled Trial

TRIAL DESIGN: Human papillomavirus infection causes verruca vulgaris. CDK9 inhibitor FIT039 inhibits DNA virus proliferation in animal models. We conducted a multicenter, single-blind, placebo-controlled, randomized phase I/II clinical trial evaluating the safety and efficacy of FIT039 against verruca vulgaris. METHODS: Target lesions were treated with liquid nitrogen once, and a FIT039 patch or placebo patch was applied for 14 days. The primary endpoint was lesion disappearance. The secondary endpoints were safety and changes in dimension, cross-sectional area, and the number of petechial lesions. RESULTS: A total of 24 participants were randomly allocated to the FIT039 (n = 13, median age, 54 years) and placebo (n = 11, median age, 62 years) groups. Verruca vulgaris did not disappear. FIT039 decreased the dimension to 76% of the initial value on day 29, followed by an increase to 98% on day 57. Placebo showed a monotonic increase to 107% on day 57. Changes in the cross-sectional area and petechiae number were comparable between the groups. CONCLUSIONS: No drug-related adverse reactions occurred. FIT039 efficacy was not determined in this study

Epigenetic modulation of Fgf21 in the perinatal mouse liver ameliorates diet-induced obesity in adulthood

The nutritional environment to which animals are exposed in early life can lead to epigenetic changes in the genome that influence the risk of obesity in later life. Here, we demonstrate that the fibroblast growth factor-21 gene (Fgf21) is subject to peroxisome proliferator-activated receptor (PPAR) α–dependent DNA demethylation in the liver during the postnatal period. Reductions in Fgf21 methylation can be enhanced via pharmacologic activation of PPARα during the suckling period. We also reveal that the DNA methylation status of Fgf21, once established in early life, is relatively stable and persists into adulthood. Reduced DNA methylation is associated with enhanced induction of hepatic FGF21 expression after PPARα activation, which may partly explain the attenuation of diet-induced obesity in adulthood. We propose that Fgf21 methylation represents a form of epigenetic memory that persists into adulthood, and it may have a role in the developmental programming of obesity