Functional redundancy between Apc and Apc2 regulates tissue homeostasis and prevents tumorigenesis in murine mammary epithelium

Aberrant Wnt signaling within breast cancer is associated with poor prognosis, but regulation of this pathway in breast tissue remains poorly understood and the consequences of immediate or long-term dysregulation remain elusive. The exact contribution of the Wnt-regulating proteins adenomatous polyposis coli (APC) and APC2 in the pathogenesis of human breast cancer are ill-defined, but our analysis of publically available array data sets indicates that tumors with concomitant low expression of both proteins occurs more frequently in the ‘triple negative’ phenotype, which is a subtype of breast cancer with particularly poor prognosis. We have used mouse transgenics to delete Apc and/or Apc2 from mouse mammary epithelium to elucidate the significance of these proteins in mammary homeostasis and delineate their influences on Wnt signaling and tumorigenesis. Loss of either protein alone failed to affect Wnt signaling levels or tissue homeostasis. Strikingly, concomitant loss led to local disruption of β-catenin status, disruption in epithelial integrity, cohesion and polarity, increased cell division and a distinctive form of ductal hyperplasia with ‘squamoid’ ghost cell nodules in young animals. Upon aging, the development of Wnt activated mammary carcinomas with squamous differentiation was accompanied by a significantly reduced survival. This novel Wnt-driven mammary tumor model highlights the importance of functional redundancies existing between the Apc proteins both in normal homeostasis and in tumorigenesis

Computational Prediction and Experimental Verification of New MAP Kinase Docking Sites and Substrates Including Gli Transcription Factors

In order to fully understand protein kinase networks, new methods are needed to identify regulators and substrates of kinases, especially for weakly expressed proteins. Here we have developed a hybrid computational search algorithm that combines machine learning and expert knowledge to identify kinase docking sites, and used this algorithm to search the human genome for novel MAP kinase substrates and regulators focused on the JNK family of MAP kinases. Predictions were tested by peptide array followed by rigorous biochemical verification with in vitro binding and kinase assays on wild-type and mutant proteins. Using this procedure, we found new ‘D-site’ class docking sites in previously known JNK substrates (hnRNP-K, PPM1J/PP2Czeta), as well as new JNK-interacting proteins (MLL4, NEIL1). Finally, we identified new D-site-dependent MAPK substrates, including the hedgehog-regulated transcription factors Gli1 and Gli3, suggesting that a direct connection between MAP kinase and hedgehog signaling may occur at the level of these key regulators. These results demonstrate that a genome-wide search for MAP kinase docking sites can be used to find new docking sites and substrates

ジシ イゾク ノ グリーフワーク オ ソクシン スル ミンカン シンコウ ノ ジッタイ

自死遺族のグリーフワークにおいて、青森県の特徴的な民間信仰である「イタコ」の、どのような支えが喪失による悲嘆を乗り越えることができたかを明らかにすることを目的に、イタコを利用したことのある自死遺族で1年以上経過した30歳代～70歳代の女性７名に聞き取り調査を行った。遺族は、イタコの口寄せによって自殺の理由を聞かされたことで、故人の人生に対する価値を見出すことができ癒された。また遺族は、【故人の生き様への共感】、さらに、【故人の加護や繋がりの実感】【相互の赦免の獲得】を経て、【生きることへの託宣】を得て、【心の浄化】ができた。The early detection of relapse in patients with schizophrenia is considered an important objective for psychiatric nurses doing home health visits. In this study, interview surveys of home health psychiatric nurses were conducted to elucidate what they watched for when monitoring these patients for signs of relapse. The results showed that when monitoring for deteriorating health, through experience, they had learned to watch for deviations from usual lifestyle patterns, worsening of patient pathological experience, loss of interest in treatment, and abnormal communication

New Stephaoxocane Alkaloids from Stephania longa

Three new stephaoxocane-type alkaloids, stephalonganines A-C (1-3), together with the known eletefine (4), were isolated from the whole plant of Stephania longa. Their structures were fully characterized spectroscopically, and the absolute configurations of the new alkaloids were assigned by comparison of their circular-dichroism (CD) data with those of 1,2-dihydrostephaoxocanine (5), in combination with 2D-NMR experiments