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Species-specific segmentation clock periods are due to differential biochemical reaction speeds 期刊论文
Science, 2020
作者:  Mitsuhiro Matsuda;  Hanako Hayashi;  Jordi Garcia-Ojalvo;  Kumiko Yoshioka-Kobayashi;  Ryoichiro Kageyama;  Yoshihiro Yamanaka;  Makoto Ikeya;  Junya Toguchida;  Cantas Alev;  Miki Ebisuya
收藏  |  浏览/下载:5/0  |  提交时间:2020/09/22
Coupling delay controls synchronized oscillation in the segmentation clock 期刊论文
NATURE, 2020
作者:  Yoshioka-Kobayashi, Kumiko;  Matsumiya, Marina;  Niino, Yusuke;  Isomura, Akihiro;  Kori, Hiroshi;  Miyawaki, Atsushi;  Kageyama, Ryoichiro
收藏  |  浏览/下载:7/0  |  提交时间:2020/07/03

Individual cellular activities fluctuate but are constantly coordinated at the population level via cell-cell coupling. A notable example is the somite segmentation clock, in which the expression of clock genes (such as Hes7) oscillates in synchrony between the cells that comprise the presomitic mesoderm (PSM)(1,2). This synchronization depends on the Notch signalling pathway  inhibiting this pathway desynchronizes oscillations, leading to somite fusion(3-7). However, how Notch signalling regulates the synchronicity of HES7 oscillations is unknown. Here we establish a live-imaging system using a new fluorescent reporter (Achilles), which we fuse with HES7 to monitor synchronous oscillations in HES7 expression in the mouse PSM at a single-cell resolution. Wild-type cells can rapidly correct for phase fluctuations in HES7 oscillations, whereas the absence of the Notch modulator gene lunatic fringe (Lfng) leads to a loss of synchrony between PSM cells. Furthermore, HES7 oscillations are severely dampened in individual cells of Lfng-null PSM. However, when Lfng-null PSM cells were completely dissociated, the amplitude and periodicity of HES7 oscillations were almost normal, which suggests that LFNG is involved mostly in cell-cell coupling. Mixed cultures of control and Lfng-null PSM cells, and an optogenetic Notch signalling reporter assay, revealed that LFNG delays the signal-sending process of intercellular Notch signalling transmission. These results-together with mathematical modelling-raised the possibility that Lfng-null PSM cells shorten the coupling delay, thereby approaching a condition known as the oscillation or amplitude death of coupled oscillators(8). Indeed, a small compound that lengthens the coupling delay partially rescues the amplitude and synchrony of HES7 oscillations in Lfng-null PSM cells. Our study reveals a delay control mechanism of the oscillatory networks involved in somite segmentation, and indicates that intercellular coupling with the correct delay is essential for synchronized oscillation.


Monitoring cells of the mouse presomitic mesoderm using the Achilles reporter fused to HES7 sheds light on the mechanisms that underpin synchronous oscillations in the expression of clock genes between neighbouring cells.


  
Fully hardware-implemented memristor convolutional neural network 期刊论文
NATURE, 2020, 577 (7792) : 641-+
作者:  Yoshioka-Kobayashi, Kumiko;  Matsumiya, Marina;  Niino, Yusuke;  Isomura, Akihiro;  Kori, Hiroshi;  Miyawaki, Atsushi;  Kageyama, Ryoichiro
收藏  |  浏览/下载:39/0  |  提交时间:2020/07/03

Memristor-enabled neuromorphic computing systems provide a fast and energy-efficient approach to training neural networks(1-4). However, convolutional neural networks (CNNs)-one of the most important models for image recognition(5)-have not yet been fully hardware-implemented using memristor crossbars, which are cross-point arrays with a memristor device at each intersection. Moreover, achieving software-comparable results is highly challenging owing to the poor yield, large variation and other non-ideal characteristics of devices(6-9). Here we report the fabrication of high-yield, high-performance and uniform memristor crossbar arrays for the implementation of CNNs, which integrate eight 2,048-cell memristor arrays to improve parallel-computing efficiency. In addition, we propose an effective hybrid-training method to adapt to device imperfections and improve the overall system performance. We built a five-layer memristor-based CNN to perform MNIST10 image recognition, and achieved a high accuracy of more than 96 per cent. In addition to parallel convolutions using different kernels with shared inputs, replication of multiple identical kernels in memristor arrays was demonstrated for processing different inputs in parallel. The memristor-based CNN neuromorphic system has an energy efficiency more than two orders of magnitude greater than that of state-of-the-art graphics-processing units, and is shown to be scalable to larger networks, such as residual neural networks. Our results are expected to enable a viable memristor-based non-von Neumann hardware solution for deep neural networks and edge computing.


  
Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8(+) cells 期刊论文
NATURE, 2020, 578 (7793) : 154-+
作者:  Diaz-Cuadros, Margarete;  Wagner, Daniel E.;  Budjan, Christoph;  Hubaud, Alexis;  Tarazona, Oscar A.;  Donelly, Sophia;  Michaut, Arthur;  Al Tanoury, Ziad;  Yoshioka-Kobayashi, Kumiko;  Niino, Yusuke;  Kageyama, Ryoichiro;  Miyawaki, Atsushi;  Touboul, Jonathan;  Pourquie, Olivier
收藏  |  浏览/下载:33/0  |  提交时间:2020/07/03

Human immunodeficiency virus (HIV) persists indefinitely in individuals with HIV who receive antiretroviral therapy (ART) owing to a reservoir of latently infected cells that contain replication-competent virus(1-4). Here, to better understand the mechanisms responsible for latency persistence and reversal, we used the interleukin-15 superagonist N-803 in conjunction with the depletion of CD8(+) lymphocytes in ART-treated macaques infected with simian immunodeficiency virus (SIV). Although N-803 alone did not reactivate virus production, its administration after the depletion of CD8(+) lymphocytes in conjunction with ART treatment induced robust and persistent reactivation of the virus in vivo. We found viraemia of more than 60 copies per ml in all macaques (n = 14  100%) and in 41 out of a total of 56 samples (73.2%) that were collected each week after N-803 administration. Notably, concordant results were obtained in ART-treated HIV-infected humanized mice. In addition, we observed that co-culture with CD8(+) T cells blocked the in vitro latency-reversing effect of N-803 on primary human CD4(+) T cells that were latently infected with HIV. These results advance our understanding of the mechanisms responsible for latency reversal and lentivirus reactivation during ART-suppressed infection.


The interleukin-15 superagonist N-803, combined with the depletion of CD8(+) lymphocytes, induced a robust and persistent reactivation of the virus in vivo in both antiretroviral-therapy-treated SIV-infected macaques and HIV-infected humanized mice.