Cell-based screen for altered nuclear phenotypes reveals senescence progression in polyploid cells after Aurora kinase B inhibition.

Cellular senescence is a widespread stress response and is widely considered to be an alternative cancer therapeutic goal. Unlike apoptosis, senescence is composed of a diverse set of subphenotypes, depending on which of its associated effector programs are engaged. Here we establish a simple and sensitive cell-based prosenescence screen with detailed validation assays. We characterize the screen using a focused tool compound kinase inhibitor library. We identify a series of compounds that induce different types of senescence, including a unique phenotype associated with irregularly shaped nuclei and the progressive accumulation of G1 tetraploidy in human diploid fibroblasts. Downstream analyses show that all of the compounds that induce tetraploid senescence inhibit Aurora kinase B (AURKB). AURKB is the catalytic component of the chromosome passenger complex, which is involved in correct chromosome alignment and segregation, the spindle assembly checkpoint, and cytokinesis. Although aberrant mitosis and senescence have been linked, a specific characterization of AURKB in the context of senescence is still required. This proof-of-principle study suggests that our protocol is capable of amplifying tetraploid senescence, which can be observed in only a small population of oncogenic RAS-induced senescence, and provides additional justification for AURKB as a cancer therapeutic target.This work was supported by the University of Cambridge, Cancer Research UK, Hutchison Whampoa; Cancer Research UK grants A6691 and A9892 (M.N., N.K., C.J.T., D.C.B., C.J.C., L.S.G, and M.S.); a fellowship from the Uehara Memorial Foundation (M.S.).This is the author accepted manuscript. The final version is available from the American Society for Cell Biology via http://dx.doi.org/10.1091/mbc.E15-01-000

How to Improve the Management of Acute Ischemic Stroke by Modern Technologies, Artificial Intelligence, and New Treatment Methods

Stroke remains one of the leading causes of death and disability in Europe. The European Stroke Action Plan (ESAP) defines four main targets for the years 2018 to 2030. The COVID-19 pandemic forced the use of innovative technologies and created pressure to improve internet networks. Moreover, 5G internet network will be helpful for the transfer and collecting of extremely big databases. Nowadays, the speed of internet connection is a limiting factor for robotic systems, which can be controlled and commanded potentially from various places in the world. Innovative technologies can be implemented for acute stroke patient management soon. Artificial intelligence (AI) and robotics are used increasingly often without the exception of medicine. Their implementation can be achieved in every level of stroke care. In this article, all steps of stroke health care processes are discussed in terms of how to improve them (including prehospital diagnosis, consultation, transfer of the patient, diagnosis, techniques of the treatment as well as rehabilitation and usage of AI). New ethical problems have also been discovered. Everything must be aligned to the concept of "time is brain"

Circadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway

肝細胞の分裂に必須の時計遺伝子 --新しい分子機能を解明、肝疾患の予防や治療にも期待--. 京都大学プレスリリース. 2017-12-25.Liver metabolism undergoes robust circadian oscillations in gene expression and enzymatic activity essential for liver homeostasis, but whether the circadian clock controls homeostatic self-renewal of hepatocytes is unknown. Here we show that hepatocyte polyploidization is markedly accelerated around the central vein, the site of permanent cell self-renewal, in mice deficient in circadian Period genes. In these mice, a massive accumulation of hyperpolyploid mononuclear and binuclear hepatocytes occurs due to impaired mitogen-activated protein kinase phosphatase 1 (Mkp1)-mediated circadian modulation of the extracellular signal-regulated kinase (Erk1/2) activity. Time-lapse imaging of hepatocytes suggests that the reduced activity of Erk1/2 in the midbody during cytokinesis results in abscission failure, leading to polyploidization. Manipulation of Mkp1 phosphatase activity is sufficient to change the ploidy level of hepatocytes. These data provide clear evidence that the Period genes not only orchestrate dynamic changes in metabolic activity, but also regulate homeostatic self-renewal of hepatocytes through Mkp1-Erk1/2 signaling pathway