PKC-δ mediates interferon-α-induced apoptosis through c-Jun NH2-terminal kinase activation

<p>Abstract</p> <p>Background</p> <p>Interferon-α (IFN-α) exerts an anti-tumor effect at least through induction of apoptosis in a variety of types including B lymphoma cells. We recently found that IFN-α induced a sustained activation of c-Jun NH₂-terminal kinase1 (JNK1), which is implicated in activation of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) promoter. In the present study, we explored upstream component(s) of the prolonged IFN-α-initiated activation of JNK1.</p> <p>Results</p> <p>IFN-α caused activation of PKC-δ in Daudi B lymphoma cells and myeloma U266 cells, as detected by Western blotting using a monoclonal antibody specific for the phosphorylated form of PKC-δ. The dominant-negative form of mutant PKC-δ (dnPKC-δ) reduced the IFN-α-induced JNK1 activation, TRAIL promoter activity, loss of mitochondrial membrane potential (ΔΨm), and increase in propidium iodide (PI) positive cells. The IFN-α-induced activation of JNK1 and the TRAIL promoter was also attenuated by the PKC-δ inhibitor rottlerin. Moreover, a constitutively active form of mutant PKC-δ enhanced the IFN-α-induced TRAIL promoter activity and loss of ΔΨm in Daudi B lymphoma cells. In addition, IFN-α-induced Ser727 phosphorylation of Stat1 was also abrogated by dnPKC-δ.</p> <p>Conclusions</p> <p>IFN-α induced JNK1 activation via PKC-δ, leading to upregulation of TRAIL. The interaction of the consequent enhanced TRAIL expression with TRAIL-receptor results in a loss of ΔΨm and increase in PI positive cells. The IFN-α-induced apoptotic events may also be affected by the Ser727-Stat1 induced by PKC-δ-mediated signaling component(s).</p

Malignant peripheral nerve sheath tumor associated with neurofibromatosis type 1, with metastasis to the heart: a case report

A rare case is presented of a 61-year-old man with a malignant peripheral nerve sheath tumor associated with neurofibromatosis type 1, with metastasis to the heart. The primary tumor originated in the right thigh in 1982. Since then, the patient has had repeated local recurrences in spite of repeated surgical treatment and adjuvant chemotherapy. He has developed previous metastases of the lung and heart. The patient died of cardiac involvement

Analysis of whole Y-chromosome sequences reveals the Japanese population history in the Jomon period

UTokyo FOCUS Press releases "Archaeological mystery solved with modern genetics : Y chromosomes reveal population boom and bust in ancient Japan" https://www.u-tokyo.ac.jp/focus/en/press/z0508_00056.htm

ERRγ agonist under mechanical stretching manifests hypertrophic cardiomyopathy phenotypes of engineered cardiac tissue through maturation

iPS細胞から成熟した人工心筋組織の作製方法の開発 肥大型心筋症の治療法開発への利用に期待. 京都大学プレスリリース. 2023-10-06.Stretching and stimulating engineered heart tissues to accurately portray hypertrophic cardiomyopathy. 京都大学プレスリリース. 2023-10-17.Engineered cardiac tissue (ECT) using human induced pluripotent stem cell-derived cardiomyocytes is a promising tool for modeling heart disease. However, tissue immaturity makes robust disease modeling difficult. Here, we established a method for modeling hypertrophic cardiomyopathy (HCM) malignant (MYH7 R719Q) and nonmalignant (MYBPC3 G115∗) pathogenic sarcomere gene mutations by accelerating ECT maturation using an ERRγ agonist, T112, and mechanical stretching. ECTs treated with T112 under 10% elongation stimulation exhibited more organized and mature characteristics. Whereas matured ECTs with the MYH7 R719Q mutation showed broad HCM phenotypes, including hypertrophy, hypercontraction, diastolic dysfunction, myofibril misalignment, fibrotic change, and glycolytic activation, matured MYBPC3 G115∗ ECTs displayed limited phenotypes, which were primarily observed only under our new maturation protocol (i.e., hypertrophy). Altogether, ERRγ activation combined with mechanical stimulation enhanced ECT maturation, leading to a more accurate manifestation of HCM phenotypes, including non-cardiomyocyte activation, consistent with clinical observations

Dry swing training with a light bat increases bat speed

Baseball training usually includes dry swing training to improve batting ability. However, no consensus has been reached on the relationship between bat weight and the increase in post-dry swing training bat speed. We hypothesized that dry swing training with a light bat would increase post dry swing training bat speed. Therefore, the purpose of this study was to examine the effect of dry swing training with a light bat on post dry swing training bat speed by comparing a light bat group with a heavy bat group. A total of 34 healthy male students from a university baseball team were randomly divided into a light bat group (n = 17) and a heavy bat group (n = 17). Subjects performed 100 dry swings per day, twice a week for eight weeks. The light bat group performed dry swing training with a 10.6 oz bat and the heavy bat group with a 38.8 oz bat. Bat speed and muscle power were measured before and after the intervention. There was no interaction between the intervention and post dry swing training bat speed, knee extension strength, shoulder horizontal flexion, or hand grip strength. There was a main effect of the intervention on post dry swing training bat speed and shoulder horizontal flexion. Bat speed increased in both groups, but without significant group differences in intervention effects. Since light bat loads in this study were very low, dry swing training with a light bat may be more effective and less strenuous

ERRγ enhances cardiac maturation with T-tubule formation in human iPSC-derived cardiomyocytes

ヒトのiPS細胞から新生児レベルまで成熟した心筋細胞を作製する. 京都大学プレスリリース. 2021-06-21.Lowering the cost of heart cell therapies. 京都大学プレスリリース. 2021-06-21.One of the earliest maturation steps in cardiomyocytes (CMs) is the sarcomere protein isoform switch between TNNI1 and TNNI3 (fetal and neonatal/adult troponin I). Here, we generate human induced pluripotent stem cells (hiPSCs) carrying a TNNI1[EmGFP] and TNNI3[mCherry] double reporter to monitor and isolate mature sub-populations during cardiac differentiation. Extensive drug screening identifies two compounds, an estrogen-related receptor gamma (ERRγ) agonist and an S-phase kinase-associated protein 2 inhibitor, that enhances cardiac maturation and a significant change to TNNI3 expression. Expression, morphological, functional, and molecular analyses indicate that hiPSC-CMs treated with the ERRγ agonist show a larger cell size, longer sarcomere length, the presence of transverse tubules, and enhanced metabolic function and contractile and electrical properties. Here, we show that ERRγ-treated hiPSC-CMs have a mature cellular property consistent with neonatal CMs and are useful for disease modeling and regenerative medicine

Associations between the orexin (hypocretin) receptor 2 gene polymorphism Val308Ile and nicotine dependence in genome-wide and subsequent association studies

Impact of the HCRTR2 gene risk variant on schizotypal personality traits (mean ± SD). (DOC 54 kb

チテキ ショウガイ ジ ニ オケル オンセツ チュウシュツ カダイ ト シリトリ カダイ ノ シュウトク ケイカ ニ カンスル ジレイ ケンキュウ

知的障害児を対象としたかな文字の読み書き学習では、音節抽出課題の指導が重要である。本研究では、音節抽出課題に先だって「かな文字カードにより単語を呈示した後、隠す」という手続きを利用して音節抽出の支援課題を設定し、その支援効果に関して検討することを目的とした。対象は、知的障害児2名（知的障害特別支援学校小学部4年生、語彙年齢4歳および7歳）とした。指導前において両対象児は、かな文字読みについてほぼ達成を示したが、音節抽出課題未達成を示した。7月から11月にかけての音節抽出指導の結果、対象児Ａ、Ｂ共に支援がない条件で、2、3音節単語の音節抽出課題の正答率が増加し、課題達成を確認できた。また、2から4音節単語の音節抽出が達成された段階の後に、しりとり課題の流暢な遂行が可能になった。これより音節抽出の支援課題の有効性を指摘できる