細辛およびその主要成分のメチルオイゲノールの鎮痛活性とその作用機序に関する研究

取得学位：博士(薬学)，学位授与番号：博甲第919号，学位授与年月日：平成19年3月22

bFGF Regulates PI3-Kinase-Rac1-JNK Pathway and Promotes Fibroblast Migration in Wound Healing

Fibroblast proliferation and migration play important roles in wound healing. bFGF is known to promote both fibroblast proliferation and migration during the process of wound healing. However, the signal transduction of bFGF-induced fibroblast migration is still unclear, because bFGF can affect both proliferation and migration. Herein, we investigated the effect of bFGF on fibroblast migration regardless of its effect on fibroblast proliferation. We noticed involvement of the small GTPases of the Rho family, PI3-kinase, and JNK. bFGF activated RhoA, Rac1, PI3-kinase, and JNK in cultured fibroblasts. Inhibition of RhoA did not block bFGF-induced fibroblast migration, whereas inhibition of Rac1, PI3-kinase, or JNK blocked the fibroblast migration significantly. PI3-kinase-inhibited cells down-regulated the activities of Rac1 and JNK, and Rac1-inhibited cells down-regulated JNK activity, suggesting that PI3-kinase is upstream of Rac1 and that JNK is downstream of Rac1. Thus, we concluded that PI3-kinase, Rac1, and JNK were essential for bFGF-induced fibroblast migration, which is a novel pathway of bFGF-induced cell migration

Tuning of Sry expression by H3K9 methylation and demethylation

Histone H3 lysine 9 (H3K9) methylation is a hallmark of heterochromatin. H3K9 demethylation is crucial in mouse sex determination; The H3K9 demethylase Jmjd1a deficiency leads to increased H3K9 methylation at the Sry locus in embryonic gonads, thereby compromising Sry expression and causing male-to-female sex reversal. We hypothesized that the H3K9 methylation level at the Sry locus is finely tuned by the balance in activities between the H3K9 demethylase Jmjd1a and an unidentified H3K9 methyltransferase to ensure correct Sry expression. Here we identified the GLP/G9a H3K9 methyltransferase complex as the enzyme catalyzing H3K9 methylation at the Sry locus. Based on this finding, we tried to rescue the sex-reversal phenotype of Jmjd1a-deficient mice by modulating GLP/G9a complex activity. A heterozygous GLP mutation rescued the sex-reversal phenotype of Jmjd1a-deficient mice by restoring Sry expression. The administration of a chemical inhibitor of GLP/G9a enzyme into Jmjd1a-deficient embryos also successfully rescued sex reversal. Our study not only reveals the molecular mechanism underlying the tuning of Sry expression but also provides proof on the principle of therapeutic strategies based on the pharmacological modulation of epigenetic balance

Personalized prediction of overall survival in patients with AML in non‐complete remission undergoing allo‐HCT

Allogenic hematopoietic stem cell transplantation (allo-HCT) is the standard treatment for acute myeloid leukemia (AML) in non-complete remission (non-CR); however, the prognosis is inconsistent. This study aimed to develop and validate nomograms and a web application to predict the overall survival (OS) of patients with non-CR AML undergoing allo-HCT (cord blood transplantation [CBT], bone marrow transplantation [BMT], and peripheral blood stem cell transplantation [PBSCT]). Data from 3052 patients were analyzed to construct and validate the prognostic models. The common significant prognostic factors among patients undergoing allo-HCT were age, performance status, percentage of peripheral blasts, cytogenetic risk, chemotherapy response, and number of transplantations. The conditioning regimen was a significant prognostic factor only in patients undergoing CBT. Compared with cyclophosphamide/total body irradiation, a conditioning regimen of ≥3 drugs, including fludarabine, with CBT exhibited the lowest hazard ratio for mortality (0.384; 95% CI, 0.266-0.554; p < 0.0001). A conditioning regimen of ≥3 drugs with CBT also showed the best leukemia-free survival among all conditioning regimens. Based on the results of the multivariable analysis, we developed prognostic models showing adequate calibration and discrimination (the c-indices for CBT, BMT, and PBSCT were 0.648, 0.600, and 0.658, respectively). Our prognostic models can help in assessing individual risks and designing future clinical studies. Furthermore, our study indicates the effectiveness of multi-drug conditioning regimens in patients undergoing CBT

Large-scale analysis of full-length cDNAs from the tomato (Solanum lycopersicum) cultivar Micro-Tom, a reference system for the Solanaceae genomics

<p>Abstract</p> <p>Background</p> <p>The Solanaceae family includes several economically important vegetable crops. The tomato (<it>Solanum lycopersicum</it>) is regarded as a model plant of the Solanaceae family. Recently, a number of tomato resources have been developed in parallel with the ongoing tomato genome sequencing project. In particular, a miniature cultivar, Micro-Tom, is regarded as a model system in tomato genomics, and a number of genomics resources in the Micro-Tom-background, such as ESTs and mutagenized lines, have been established by an international alliance.</p> <p>Results</p> <p>To accelerate the progress in tomato genomics, we developed a collection of fully-sequenced 13,227 Micro-Tom full-length cDNAs. By checking redundant sequences, coding sequences, and chimeric sequences, a set of 11,502 non-redundant full-length cDNAs (nrFLcDNAs) was generated. Analysis of untranslated regions demonstrated that tomato has longer 5'- and 3'-untranslated regions than most other plants but rice. Classification of functions of proteins predicted from the coding sequences demonstrated that nrFLcDNAs covered a broad range of functions. A comparison of nrFLcDNAs with genes of sixteen plants facilitated the identification of tomato genes that are not found in other plants, most of which did not have known protein domains. Mapping of the nrFLcDNAs onto currently available tomato genome sequences facilitated prediction of exon-intron structure. Introns of tomato genes were longer than those of Arabidopsis and rice. According to a comparison of exon sequences between the nrFLcDNAs and the tomato genome sequences, the frequency of nucleotide mismatch in exons between Micro-Tom and the genome-sequencing cultivar (Heinz 1706) was estimated to be 0.061%.</p> <p>Conclusion</p> <p>The collection of Micro-Tom nrFLcDNAs generated in this study will serve as a valuable genomic tool for plant biologists to bridge the gap between basic and applied studies. The nrFLcDNA sequences will help annotation of the tomato whole-genome sequence and aid in tomato functional genomics and molecular breeding. Full-length cDNA sequences and their annotations are provided in the database KaFTom <url>http://www.pgb.kazusa.or.jp/kaftom/</url> via the website of the National Bioresource Project Tomato <url>http://tomato.nbrp.jp</url>.</p

KaPPA-View4: a metabolic pathway database for representation and analysis of correlation networks of gene co-expression and metabolite co-accumulation and omics data

Correlations of gene-to-gene co-expression and metabolite-to-metabolite co-accumulation calculated from large amounts of transcriptome and metabolome data are useful for uncovering unknown functions of genes, functional diversities of gene family members and regulatory mechanisms of metabolic pathway flows. Many databases and tools are available to interpret quantitative transcriptome and metabolome data, but there are only limited ones that connect correlation data to biological knowledge and can be utilized to find biological significance of it. We report here a new metabolic pathway database, KaPPA-View4 (http://kpv.kazusa.or.jp/kpv4/), which is able to overlay gene-to-gene and/or metabolite-to-metabolite relationships as curves on a metabolic pathway map, or on a combination of up to four maps. This representation would help to discover, for example, novel functions of a transcription factor that regulates genes on a metabolic pathway. Pathway maps of the Kyoto Encyclopedia of Genes and Genomes (KEGG) and maps generated from their gene classifications are available at KaPPA-View4 KEGG version (http://kpv.kazusa.or.jp/kpv4-kegg/). At present, gene co-expression data from the databases ATTED-II, COXPRESdb, CoP and MiBASE for human, mouse, rat, Arabidopsis, rice, tomato and other plants are available

ヤマナシケン コスゲムラ ニ オケル ジキュウテキ トチリヨウ ノ ジッタイ ─イキサツ・ジッタイ・カダイ─

山村問題のうち自給的農業の状況を把握するために,山梨県北都留郡小菅村(以後:本村と呼ぶ)を対象にアンケート調査・ヒアリング調査を実施し,その結果として,本村の「自給的農業」のあらましについて論じるとともに,そこから見いだせる農法や生活過程を観察し,今まで認識されてこなかった現代山村の盲点について指摘する。本村は,本畑,切替え畑(焼畑用地),山林,採草地の4種類を活用してきた。本村では古くから主食はサトイモであり,他に雑穀類を焼畑によって補ってきた。1782年から1788年にかけて発生した飢饉を受け,代官中井清太夫(1784～1794年)が,長崎より耐寒品種であるバレイショを導入し,凶作年に備えた。そのため,本来主食であったサトイモよりバレイショのほうが作付量・収穫量ともに多くなった。地租改正を経て,H集落では1933年以後コンニャクを栽培し販売することで白米食を実現するなど,焼畑や麦作をやめる地域もでてきた。さらに養蚕も換金性があることから,焼畑から桑畑に転換する場合が多くなった。ところが,戦時および終戦期の食料難を迎えると焼畑が盛んに行われるようになった。しかし,1970年代を境に焼畑はおこなわれなくなり,その場所にスギ・ヒノキが植栽された。元々は,森林を伐採し木炭を製造し販売し,森林伐採跡地に焼畑を行う方法をとっていた。そこで,今日,自給的農業が成立しているのに焼畑が成立せず,「切替え畑」ではなく本畑を使用するのみなのか,農家への調査により歴史的意味合いにおいて検証した。また,自給的農家があるということが,耕作地保全に役立つ根拠を耕作活動から見いだした。We conducted a hearing investigation on self-support farming in Kosuge village, Kitatsuru District, Yamanashi Prefecture. In this paper, we described the overview of "subsistence farming" in Motomura and the farming method and life styles of the villagers there in order to understand the problems of mountain villages. In the old days, the villagers here employed four types of farming methods : field-slash-and-burn-forest-meadow. Staple food in this village was taro and grains or coarse cereal gained through slash-and-burn farming. From 1782 to 1788, a great famine occurred. So, in order to prepare against the famine that might occur, Magistrate Kiyoshitayu Nakai (1784-1794) introduced the potato from Nagasaki ; a breed with enough cold resistance. Nowadays, there is more potato cropping than taro, which was originally the staple food of the villagers. After the land tax amendment, there appeared settlements that began to stop slash-and-burn farming and wheat crop, such as Settlement H, where people were able to attain white rice by cultivating and selling amorphophallus konjac. Furthermore, as silkworm breeding attained high profitability, people began to change their style of life from slash-and-burn farming. However, during and after World War II, a time of food shortage, the villagers once again began to use the slash-and-burn method. However, since the 1970s, slash-and-burn fields were transformed into forests of cedar and cypress. This paper focuseson the reasons why slash-and-burn method is rarely up taken in spite of the fact that self-support farming is still popular. Also, the importance of policy support is emphasized in order to make self-support farming profitable for the preservation of cultivated lands

Azimuthal anisotropy of charged jet production in root s(NN)=2.76 TeV Pb-Pb collisions

We present measurements of the azimuthal dependence of charged jet production in central and semi-central root s(NN) = 2.76 TeV Pb-Pb collisions with respect to the second harmonic event plane, quantified as nu(ch)(2) (jet). Jet finding is performed employing the anti-k(T) algorithm with a resolution parameter R = 0.2 using charged tracks from the ALICE tracking system. The contribution of the azimuthal anisotropy of the underlying event is taken into account event-by-event. The remaining (statistical) region-to-region fluctuations are removed on an ensemble basis by unfolding the jet spectra for different event plane orientations independently. Significant non-zero nu(ch)(2) (jet) is observed in semi-central collisions (30-50% centrality) for 20 <p(T)(ch) (jet) <90 GeV/c. The azimuthal dependence of the charged jet production is similar to the dependence observed for jets comprising both charged and neutral fragments, and compatible with measurements of the nu(2) of single charged particles at high p(T). Good agreement between the data and predictions from JEWEL, an event generator simulating parton shower evolution in the presence of a dense QCD medium, is found in semi-central collisions. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe