PPARα as a Transcriptional Regulator for Detoxification of Plant Diet-Derived Unfavorable Compounds

Plants contain potentially toxic compounds for animals and animals have developed physiological strategies to detoxify the ingested toxins during evolution. Feeding mice with various plant seeds and grains showed unexpected result that only sesame killed PPARα-null mice but not wild-type mice at all. A detailed analysis of this observation revealed that PPARα is involved in the metabolism of toxic compounds from plants as well as endobiotic substrates by inducing phase I and phase II detoxification enzymes. PPARα plays a vital role in direct or indirect activation of the relevant genes via the complex network among other xenobiotic nuclear receptors. Thus, PPARα plays its wider and more extensive role in energy metabolism from natural food intake to fat storage than previously thought

1950年代ドイツ連邦共和国におけるキリスト教民主同盟（CDU）の住宅政策 ： カトリシズムの影響を中心に

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 姫岡 とし子, 東京大学教授 武川 正吾, 東京大学准教授 勝田 俊輔, 東京大学准教授 池田 嘉郎, 大阪市立大学教授 北村 昌史University of Tokyo(東京大学

Spliced Leader Trapping Reveals Widespread Alternative Splicing Patterns in the Highly Dynamic Transcriptome of Trypanosoma brucei

Trans-splicing of leader sequences onto the 5′ends of mRNAs is a widespread phenomenon in protozoa, nematodes and some chordates. Using parallel sequencing we have developed a method to simultaneously map 5′splice sites and analyze the corresponding gene expression profile, that we term spliced leader trapping (SLT). The method can be applied to any organism with a sequenced genome and trans-splicing of a conserved leader sequence. We analyzed the expression profiles and splicing patterns of bloodstream and insect forms of the parasite Trypanosoma brucei. We detected the 5′ splice sites of 85% of the annotated protein-coding genes and, contrary to previous reports, found up to 40% of transcripts to be differentially expressed. Furthermore, we discovered more than 2500 alternative splicing events, many of which appear to be stage-regulated. Based on our findings we hypothesize that alternatively spliced transcripts present a new means of regulating gene expression and could potentially contribute to protein diversity in the parasite. The entire dataset can be accessed online at TriTrypDB or through: http://splicer.unibe.ch/

Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles

<div><p>Recent development of benzoxaborole-based chemistry gave rise to a collection of compounds with great potential in targeting diverse infectious diseases, including human African Trypanosomiasis (HAT), a devastating neglected tropical disease. However, further medicinal development is largely restricted by a lack of insight into mechanism of action (MoA) in pathogenic kinetoplastids. We adopted a multidisciplinary approach, combining a high-throughput forward genetic screen with functional group focused chemical biological, structural biology and biochemical analyses, to tackle the complex MoAs of benzoxaboroles in <i>Trypanosoma brucei</i>. We describe an oxidative enzymatic pathway composed of host semicarbazide-sensitive amine oxidase and a trypanosomal aldehyde dehydrogenase TbALDH3. Two sequential reactions through this pathway serve as the key underlying mechanism for activating a series of 4-aminomethylphenoxy-benzoxaboroles as potent trypanocides; the methylamine parental compounds as pro-drugs are transformed first into intermediate aldehyde metabolites, and further into the carboxylate metabolites as effective forms. Moreover, comparative biochemical and crystallographic analyses elucidated the catalytic specificity of TbALDH3 towards the benzaldehyde benzoxaborole metabolites as xenogeneic substrates. Overall, this work proposes a novel drug activation mechanism dependent on both host and parasite metabolism of primary amine containing molecules, which contributes a new perspective to our understanding of the benzoxaborole MoA, and could be further exploited to improve the therapeutic index of antimicrobial compounds.</p></div

Tensile and bending properties of biaxial weft-knitted and cross-ply thermoplastic composites

In this study, within the scope of experiments, two kinds of biaxial weft-knitted (BWK) fabrics with aramid (AR) and polyamide 66 (PA66) stitch fibers were used as reinforcement systems to fabricate thermoplastic composites with PA66 resin yarn. Then final composite became BWK with AR stitch yarn and cross-ply. The mechanical properties of composites were investigated by conducting tensile and three-point bending tests on specimens. In all specimens, PA66 was commingled with AR yarn. AR was used as reinforcement. In preliminary studies, AR unidirectional composites with AR/PA66 commingled fibers and with various twisting angles were produced and appropriate twisting angle was found by conducting tensile and three-point bending impact tests on specimens. Because of the higher volume fraction of the cross-ply composites, tensile and three-point bending properties of the cross-ply composite structures had higher than the BWK composites with the AR stitch yarn