Copy number loss of (src homology 2 domain containing)-transforming protein 2 (SHC2) gene: discordant loss in monozygotic twins and frequent loss in patients with multiple system atrophy

<p>Abstract</p> <p>Background</p> <p>Multiple system atrophy (MSA) is a sporadic disease. Its pathogenesis may involve multiple genetic and nongenetic factors, but its etiology remains largely unknown. We hypothesized that the genome of a patient with MSA would demonstrate copy number variations (CNVs) in the genes or genomic regions of interest. To identify genomic alterations increasing the risk for MSA, we examined a pair of monozygotic (MZ) twins discordant for the MSA phenotype and 32 patients with MSA.</p> <p>Results</p> <p>By whole-genome CNV analysis using a combination of CNV beadchip and comparative genomic hybridization (CGH)-based CNV microarrays followed by region-targeting, high-density, custom-made oligonucleotide tiling microarray analysis, we identified disease-specific copy number loss of the (Src homology 2 domain containing)-transforming protein 2 (<it>SHC2</it>) gene in the distal 350-kb subtelomeric region of 19p13.3 in the affected MZ twin and 10 of the 31 patients with MSA but not in 2 independent control populations (<it>p </it>= 1.04 × 10^-8, odds ratio = 89.8, Pearson's chi-square test).</p> <p>Conclusions</p> <p>Copy number loss of <it>SHC2 </it>strongly indicates a causal link to MSA. CNV analysis of phenotypically discordant MZ twins is a powerful tool for identifying disease-predisposing loci. Our results would enable the identification of novel diagnostic measure, therapeutic targets and better understanding of the etiology of MSA.</p

ニジュウセイキ ゼンハン ノ カワサキ シ ニ オケル トシ ギョウセイ ノ テンカイ カテイ : ジュウタク セイサク オ チュウシン ニ

The purpose of this article is to consider the development process of Kawasaki City’s urban administration in the firsthalf of the 20th century. In early 1910’s Kawasaki City, the industrialization have progressed rapidly and the need ofestablishment of city administration: urban planning like land readjustment and zoning, social service like housing supply.In large cities, technical bureaucrats（technocrat）who specialized in urban administration began to play an importantrole in municipal administration in the 1920’s in place of the traditional administration by famous people. On the otherhand, in Kawasaki City, human resources “regional technocrats” capable of taking charge of urban administration hadbeen growing. It was in the late 1930s and early 1940s, when the Sino-Japanese war began and munitions factoriesexpanded inland, that they actually planned and executed urban planning and housing supply. Based on the policy ofKanagawa Prefecture, they were actively involved in the Housing Company collective housing development project forlaborers, and formed the largest residential area of the Company in “Huruichiba” district. And then, the “regionaltechnocrats” that grew up during this period will play an especially important role in the postwar reconstruction

A Zebrafish Chemical Suppressor Screening Identifies Small Molecule Inhibitors of the Wnt/β-catenin Pathway

SummaryGenetic screening for suppressor mutants has been successfully used to identify important signaling regulators. Using an analogy to genetic suppressor screening, we developed a chemical suppressor screening method to identify inhibitors of the Wnt/β-catenin signaling pathway. We used zebrafish embryos in which chemically induced β-catenin accumulation led to an “eyeless” phenotype and conducted a pilot screening for compounds that restored eye development. This approach allowed us to identify geranylgeranyltransferase inhibitor 286 (GGTI-286), a geranylgeranyltransferase (GGTase) inhibitor. Our follow-up studies showed that GGTI-286 reduces nuclear localization of β-catenin and transcription dependent on β-catenin/T cell factor in mammalian cells. In addition to pharmacological inhibition, GGTase gene knockdown also attenuates the nuclear function of β-catenin. Overall, we validate our chemical suppressor screening as a method for identifying Wnt/β-catenin pathway inhibitors and implicate GGTase as a potential therapeutic target for Wnt-activated cancers

Clinical and Pathological Benefits of Edaravone for Alzheimer's Disease with Chronic Cerebral Hypoperfusion in a Novel Mouse Model

Alzheimer's disease (AD) and chronic cerebral hypoperfusion (CCH) often coexist in dementia patients in aging societies. The hallmarks of AD including amyloid-β (Aβ)/phosphorylated tau (pTau) and pathology-related events such as neural oxidative stress and neuroinflammation play critical roles in pathogenesis of AD with CCH. A large number of lessons from failures of drugs targeting a single target or pathway on this so complicated disease indicate that disease-modifying therapies targeting multiple key pathways hold potent potential in therapy of the disease. In the present study, we used a novel mouse model of AD with CCH to investigate a potential therapeutic effect of a free radical scavenger, Edaravone (EDA) on AD with CCH via examining motor and cognitive capacity, AD hallmarks, neural oxidative stress, and neuroinflammation. Compared with AD with CCH mice at 12 months of age, EDA significantly improved motor and cognitive deficits, attenuated neuronal loss, reduced Aβ/pTau accumulation, and alleviated neural oxidative stress and neuroinflammation. These findings suggest that EDA possesses clinical and pathological benefits for AD with CCH in the present mouse model and has a potential as a therapeutic agent for AD with CCH via targeting multiple key pathways of the disease pathogenesis

A pneumococcal meningoencephalitis with a small spleen

Streptococcus pneumoniae is a major cause of bacterial meningitis usually in children or elder adults. We report a case of a 38-year-old man having pneumococcal meningoencephalitis with a small spleen (35 cm(3)), compared to seven previous patients with pneumococcal meningitis in our department. Among the eight patients, four cases were due to sinusitis, but the origin could not be identified in the other four cases, including the present case who was the youngest patient with the smallest splenic size. Of interest in the present analysis was the negative or positive correlation between splenic size and age, with or without sinusitis. This is the first report on pneumococcal meningoencephalitis that takes into consideration age, splenic size, and the origin of infection

Intracrine activity involving NAD-dependent circadian steroidogenic activity governs age-associated meibomian gland dysfunction

新たなイントラクライン機構を用いた加齢性眼疾患治療へ --眼局所のホルモンの加齢変化とサーカディアンリズムが鍵--. 京都大学プレスリリース. 2022-02-14.Canonically, hormones are produced in the endocrine organs and delivered to target tissues. However, for steroids, the concept of tissue intracrinology, whereby hormones are produced in the tissues where they exert their effect without release into circulation, has been proposed, but its role in physiology/disease remains unclear. The meibomian glands in the eyelids produce oil to prevent tear evaporation, which reduces with aging. Here, we demonstrate that (re)activation of local intracrine activity through nicotinamide adenine dinucleotide (NAD+)-dependent circadian 3β-hydroxyl-steroid dehydrogenase (3β-HSD) activity ameliorates age-associated meibomian gland dysfunction and accompanying evaporative dry eye disease. Genetic ablation of 3β-HSD nullified local steroidogenesis and led to atrophy of the meibomian gland. Conversely, reactivation of 3β-HSD activity by boosting its coenzyme NAD+ availability improved glandular cell proliferation and alleviated the dry eye disease phenotype. Both women and men express 3β-HSD in the meibomian gland. Enhancing local steroidogenesis may help combat age-associated meibomian gland dysfunction

On Object specification of Action

We observed separating fish action. Subjects were a right-handed graduate student and a right-handed cerebral infracted patient. A graduate student separated dried horse mackereles two times by her right and left hand with chopsticks. A patient separated four times over 6 months by left \u27nonparalysis\u27hand with also chop-sticks. We analyzed 6 actions video taped in these way : time, number of hand contacts with fish, number of functional acts that succeed to separate a piece of flesh. Contacts were divided in four sub-action categories, to separate fish, to separate bone or peel a skin, to put in order whole body and to arrange separated fleshes, bones and skins (see Table. 1). Organization of a sequential action process of these sub-action categories and an adjacent order of functional acts in each trials were showed Fig.1 to 12. Results showed that several anatomical structures of fish and variable action processes to separate fish were reciprocally determined and emerged a unique coordinated fish-action encounter

成人看護学分野における技術演習教授法の検討 －看護援助の対象となる人を生活者として捉える技術演習の展開－

　本学部では1年生から看護技術教育が開始されるが，看護技術を専門に教授する領域を持たない教育体制の特徴がある．この特徴を踏まえて技術演習に関する検討を行い，学生は科目同士の関連性を見出しにくいという課題が明らかになった．　本稿では，3年生開講の「治療療養支援技術演習」を担当する教員が，ディスカッションを通じて考案した，「人を生活者として捉える」技術演習の展開方法について報告する．　「治療療養支援技術演習」は，「診療に伴う看護技術」を教授する科目に該当する．今回，看護援助の対象は生活者であると捉え，ヴァージニア・ヘンダーソンの14項目の日常生活行動の視点をもった演習を展開することとした．さらに，共通のフレームワークに沿って授業指導案を作成することで，学生が共通性と相違性を理解しやすいよう工夫した．授業指導案は，1）到達目標，2）ヘンダーソンの14 項目で該当する生活行動，3）ヘンダーソンの項目が満たされていない原因，4）援助方法全般の中で当該技術の位置づけ，5）事前・事後課題の内容，6）必要物品，7）人員配置，8）技術テストの評価ポイントの8項目で構成される．　今回，全ての看護技術は対象者の生活行動を補うためのものであり，対象者が生活者であることを学生が理解しやすい授業設計を検討した．本科目は平成29年度の開講であり，授業指導案の効果を現時点では評価できない．今後は教授する際のキーポイントをより明確にし，学生の理解度を評価することで技術教育方法の妥当性の確認が必要である