数理モデルを用いたヒト血糖値恒常性制御システムの解析

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 深田 吉孝, 東京大学教授 黒田 真也, 東京大学教授 飯野 雄一, 東京大学准教授 朴 民根, 東京大学准教授 石谷 隆一郎University of Tokyo(東京大学

Effects of Fluoranthene, a Polycyclic Aromatic Hydrocarbon, on cAMP-Dependent Anion Secretion in Human Airway Epithelia

ABSTRACT The human respiratory tract is constantly exposed to polycyclic aromatic hydrocarbons (PAHs) through inhalation of atmospheric pollutants. We examined the effects of three PAHs (benzo[a]pyrene, anthracene, and fluoranthene) on the airway ion transport, which is essential for lung defense and normal airway function, using human airway epithelia (Calu-3). These three PAHs had no significant effect on the basal short-circuit current (I sc ). However, fluoranthene (1-100 M) applied in the apical compartment potentiated I sc in response to cAMP-related agents (isoproterenol, forskolin, and 8-bromo-cAMP). The effects of fluoranthene were unaffected by ellipticine, a PAH receptor antagonist. Estimation of the anionic composition of I sc revealed that isoproterenol increased both HCO 3 Ϫ and Cl

Contribution of the institutions in the Northern region of Brazil to the development of plant cultivars and their impact on agriculture

This paper describes the development of breeding programs in northern Brazil and their main impacts on agriculture. Their contribution to the breeding of the species palm oil, acai fruit, cacao, cupuaçu, guarana, tomato, camu-camu, cocona, peach palm, and rubber was laid out in detail. Advances in breeding programs of institutions such as Embrapa, Ceplac, Inpa, and Universities require investments in infrastructure and in human and financial resources to ensure continuity and efficiency in economic, social and environmental gains. The improvement of native species, the main focus of the breeding programs of the institutions in the Northern region of Brazil, is a form of exploiting the Amazonian biodiversity for the benefit of society. Therefore, policies to foster research institutions should be a subject of deliberation and action of the scientific and technological community in Brazil

Phosphoinositide 3-Kinaseγ Controls the Intracellular Localization of CpG to Limit DNA-PKcs-Dependent IL-10 Production in Macrophages

Synthetic oligodeoxynucleotides containing unmethylated CpG motifs (CpG) stimulate innate immune responses. Phosphoinositide 3-kinase (PI3K) has been implicated in CpG-induced immune activation; however, its precise role has not yet been clarified. CpG-induced production of IL-10 was dramatically increased in macrophages deficient in PI3Kγ (p110γ−/−). By contrast, LPS-induced production of IL-10 was unchanged in the cells. CpG-induced, but not LPS-induced, IL-10 production was almost completely abolished in SCID mice having mutations in DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Furthermore, wortmannin, an inhibitor of DNA-PKcs, completely inhibited CpG-induced IL-10 production, both in wild type and p110γ−/− cells. Microscopic analyses revealed that CpG preferentially localized with DNA-PKcs in p110γ−/− cells than in wild type cells. In addition, CpG was preferentially co-localized with the acidic lysosomal marker, LysoTracker, in p110γ−/− cells, and with an early endosome marker, EEA1, in wild type cells. Over-expression of p110γ in Cos7 cells resulted in decreased acidification of CpG containing endosome. A similar effect was reproduced using kinase-dead mutants, but not with a ras-binding site mutant, of p110γ. Thus, it is likely that p110γ, in a manner independent of its kinase activity, inhibits the acidification of CpG-containing endosomes. It is considered that increased acidification of CpG-containing endosomes in p110γ−/− cells enforces endosomal escape of CpG, which results in increased association of CpG with DNA-PKcs to up-regulate IL-10 production in macrophages

Analysis of Expressed Sequence Tags from the Fungus Aspergillus oryzae Cultured Under Different Conditions

We performed random sequencing of cDNAs from nine biologically or industrially important cultures of the industrially valuable fungus Aspergillus oryzae to obtain expressed sequence tags (ESTs). Consequently, 21 446 raw ESTs were accumulated and subsequently assembled to 7589 non-redundant consensus sequences (contigs). Among all contigs, 5491 (72.4%) were derived from only a particular culture. These included 4735 (62.4%) singletons, i.e. lone ESTs overlapping with no others. These data showed that consideration of culture grown under various conditions as cDNA sources enabled efficient collection of ESTs. BLAST searches against the public databases showed that 2953 (38.9%) of the EST contigs showed significant similarities to deposited sequences with known functions, 793 (10.5%) were similar to hypothetical proteins, and the remaining 3843 (50.6%) showed no significant similarity to sequences in the databases. Culture-specific contigs were extracted on the basis of the EST frequency normalized by the total number for each culture condition. In addition, contig sequences were compared with sequence sets in eukaryotic orthologous groups (KOGs), and classified into the KOG functional categories

Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, <scp>genotype–phenotype</scp> correlations and common mechanisms

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (&gt;60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS‐like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or “DTRs”). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype–phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population