From clean room to machine room: commissioning of the first-generation BrainScaleS wafer-scale neuromorphic system

The first-generation of BrainScaleS, also referred to as BrainScaleS-1, is a neuromorphic system for emulating large-scale networks of spiking neurons. Following a ‘physical modeling’ principle, its VLSI circuits are designed to emulate the dynamics of biological examples: analog circuits implement neurons and synapses with time constants that arise from their electronic components’ intrinsic properties. It operates in continuous time, with dynamics typically matching an acceleration factor of 10 000 compared to the biological regime. A fault-tolerant design allows it to achieve wafer-scale integration despite unavoidable analog variability and component failures. In this paper, we present the commissioning process of a BrainScaleS-1 wafer module, providing a short description of the system’s physical components, illustrating the steps taken during its assembly and the measures taken to operate it. Furthermore, we reflect on the system’s development process and the lessons learned to conclude with a demonstration of its functionality by emulating a wafer-scale synchronous firing chain, the largest spiking network emulation ran with analog components and individual synapses to date

Myc Is Required for Activation of the ATM-Dependent Checkpoints in Response to DNA Damage

Background: The MYC protein controls cellular functions such as differentiation, proliferation, and apoptosis. In response to genotoxic agents, cells overexpressing MYC undergo apoptosis. However, the MYC-regulated effectors acting upstream of the mitochondrial apoptotic pathway are still unknown. Principal Findings: In this study, we demonstrate that expression of Myc is required to activate the Ataxia telangiectasia mutated (ATM)-dependent DNA damage checkpoint responses in rat cell lines exposed to ionizing radiation (IR) or the bacterial cytolethal distending toxin (CDT). Phosphorylation of the ATM kinase and its downstream effectors, such as histone H2AX, were impaired in the myc null cell line HO15.19, compared to the myc positive TGR-1 and HOmyc3 cells. Nuclear foci formation of the Nijmegen Breakage Syndrome (Nbs) 1 protein, essential for efficient ATM activation, was also reduced in absence of myc. Knock down of the endogenous levels of MYC by siRNA in the human cell line HCT116 resulted in decreased ATM and CHK2 phosphorylation in response to irradiation. Conversely, cell death induced by UV irradiation, known to activate the ATR-dependent checkpoint, was similar in all the cell lines, independently of the myc status. Conclusion: These data demonstrate that MYC contributes to the activation of the ATM-dependent checkpoint responses, leading to cell death in response to specific genotoxic stimuli.Swedish Cancer SocietySwedish Research Counci

<i>myc</i> deletion does not alter cell death kinetics upon UV irradiation.

<p>TGR-1, the <i>myc</i> reconstituted cells HOmyc3, and the <i>myc</i> null HO15.19 cells were left untreated or exposed to UV irradiation and further incubated in complete medium for the indicated periods of time. <b>A</b>) Analysis of the cell cycle distribution assessed by PI staining and flow cytometry as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008924#s2" target="_blank">Material and Methods</a>. <b>B</b>) Phase contrast micrographs of the cells taken at the indicated time points (Magnification 40×). One out of three independent experiments is shown.</p

<i>myc</i> deletion impairs Nbs1 foci formation in response to DNA damage.

<p>TGR-1, the <i>myc</i> reconstituted HOmyc3, and the <i>myc</i> null HO15.19 cells were exposed to bacterial lysates (1∶2000) expressing the mutant (CTR) or the wild type form (CDT) of <i>H. hepaticus</i> CDT, or irradiated (IR, 20 Gy) and further incubated in complete medium for the indicated periods of time. The Nbs1 protein was detected by indirect immunostaining, as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008924#s2" target="_blank">Material and Methods</a>. The figure shows the sub-cellular distribution of Nbs1 at 2h post-treatment.</p

<i>myc</i> deletion delays cell death upon CDT intoxication.

<p>TGR-1, the <i>myc</i> reconstituted cells HOmyc3, and the <i>myc</i> null HO15.19 cells were exposed to bacterial lysates (1∶2000) expressing the mutant (CTR) or the wild type form (CDT) of <i>H. hepaticus</i> CDT and further incubated in complete medium for the indicated periods of time. <b>A</b>) Analysis of the cell cycle distribution assessed by PI staining and flow cytometry as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008924#s2" target="_blank">Material and Methods</a>. <b>B</b>) Phase contrast micrographs of the cells taken at the indicated time points (Magnification 40×). One out of three independent experiments is shown.</p

Knock down of MYC expression decreases activation of ATM, CHK2 and p53.

<p><b>A</b>) HCT116 cells were transfected either with the control GFP-specific (CTR) or MYC specific siRNA for 48h. The expression of MYC was assessed by immunoprecipitation and western-blot analysis. One out of three independent experiments is shown. <b>B</b>) HCT116 cells, transfected either with the GFP-specific (CTR) or MYC specific siRNA were left untreated or exposed to IR (20 Gy), and further incubated in complete medium for the indicated periods of time. The levels of phosphorylation of ATM, CHK2 and p53 were assessed by western blot analysis. Actin and total ATM were used as an internal loading control. One out of three independent experiments is shown.</p

Activation of ATM and ATM-dependent responses upon induction of DNA damage is Myc dependent.

<p>TGR-1, HOmyc3, and HO15.19 cells were left untreated or exposed to IR (20Gy), and further incubated in complete medium for 2h. The levels of phospho-ATM and phospho-H2AX (γH2AX) were assessed by western blot analysis. Actin and total ATM were used as internal loading controls. One of three experiments is shown.</p

<i>myc</i> deletion prevents p53 stabilization in response to DNA damage.

<p><b>A</b>) TGR-1 and the <i>myc</i> reconstituted HOmyc3 cells were left untreated or exposed to IR (20 Gy) for the indicated periods of time. The levels of p53 were assessed by western blot analysis. <b>B</b>) TGR-1, the <i>myc</i> reconstituted HOmyc3 and the HO15.19 cells were left untreated or exposed to IR (20 Gy) for the indicated periods of time. The levels of p53 were assessed by western blot analysis. Actin was used as an internal loading control. One out of three independent experiments is shown.</p

<i>myc</i> deletion delays cell death upon irradiation.

<p><b>A</b>) The levels of the endogenous Myc protein were assessed by immunoprecipitation followed by western blot analysis in TGR-1, the <i>myc</i> reconstituted cells HOmyc3, and the <i>myc</i> null HO15.19 cells using α-Myc antibodies. Expression of actin in total cell lysates was used as control. <b>B</b>) TGR-1, the <i>myc</i> reconstituted cells HOmyc3, and the <i>myc</i> null HO15.19 cells were left untreated or irradiated (20Gy) and further incubated in complete medium for the indicated periods of time. Analysis of the cell cycle distribution was assessed by PI staining and flow cytometry as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008924#s2" target="_blank">Material and Methods</a>. One out of four independent experiments is shown.</p

Role of MYC in the regulation of the DNA damage checkpoint responses.

<p>In response to IR or CDT, MYC contributes to activation of the ATM-dependent responses, leading to induction of apotosis. These pathways are delayed upon MYC homozygote deletion or iRNA-mediated knock down.</p