CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases

Contributions of biogenic material to the atmospheric ice-nucleating particle population in North Western Europe

A minute fraction of atmospheric particles exert a disproportionate effect on the phase of mixed-phase clouds by acting as ice-nucleating particles (INPs). To understand the effects of these particles on weather and climate, both now and into the future, we must first develop a quantitative understanding of the major INP sources worldwide. Previous work has demonstrated that aerosols such as desert dusts are globally important INPs, but the role of biogenic INPs is unclear, with conflicting evidence for their importance. Here, we show that at a temperate site all INPs active above −18 °C at concentrations >0.1 L−1 are destroyed on heating, consistent with these INPs being of biological origin. Furthermore, we show that a global model of desert dust INPs dramatically underestimates the measured INP concentrations, but is consistent with the thermally-stable component. Notably, the heat sensitive INPs are active at temperatures where shallow cloud layers in Northern Europe are frequently observed to glaciate. Hence, we suggest that biogenic material is important for primary ice production in this region. The prevalence of heat sensitive, most likely biogenic, INPs in this region highlights that, as a community, we need to quantify the sources and transport of these particles as well as determine their atmospheric abundance across the globe and at cloud altitudes

Electron cyclotron heating and current drive program for KSTAR based on the 170-GHz gyrotron

Electron cyclotron heating and current drive (ECH/ECCD) has become an essential tool for fusion plasma research in toroidal devices. In the Korea Superconducting Tokamak Advanced Research (KSTAR) tokamak, development of a high power and multifrequency ECH/ECCD system is in progress. The multiple frequency sources employed in KSTAR (84 GHz and 110 GHz have been used, and 170 GHz and possibly 140 GHz are planned) support the wide range of operating magnetic fields from similar to 1.5 to 3.5 T. In particular, 170-GHz power, which will be used on ITER, corresponds to the second harmonic of the cyclotron frequency for the KSTAR operating range from 2.5 to 3.5 T. This frequency will be mainly used for control of the local plasma current profile, in order to manipulate the internal magnetohydrodynamic instabilities such as the sawtooth and neoclassical tearing mode, which can be harmful to steady-state high-beta operation. This paper presents the status of the KSTAR ECH/ECCD program and the ray-tracing calculations of the 170-GHz electron cyclotron wave propagation for various plasma conditions in KSTAR. In the ray-tracing simulation, the TORAY-GA ray-tracing code is used to study the dependence of the ECH/ECCD on the plasma profiles as a function of the beam aiming angles.X118sciescopu

Extracellular ATP mediates necrotic cell swelling in SN4741 dopaminergic neurons through P2X(7) receptors

Extracellular ATP has recently been identified as an important regulator of cell death in response to pathological insults. When SN4741 cells, which are dopaminergic neurons derived from the substantia nigra of transgenic mouse embryos, are exposed to ATP, cell death occurs. This cell death is associated with prominent cell swelling, loss of ER integrity, the formation of many large cytoplasmic vacuoles, and subsequent cytolysis and DNA release. In addition, the cleavage of caspase-3, a hallmark of apoptosis, is induced by ATP treatment. However, caspase inhibitors do not overcome ATP-induced cell death, indicating that both necrosis and apoptosis are associated with ATP-induced cell death and suggesting that a necrotic event might override the apoptotic process. In this study we also found that P2X(7) receptors (P2X(7)Rs) are abundantly expressed in SN4741 cells, and both ATP-induced swelling and cell death are reversed by pretreatment with the P2X(7)Rs antagonist, KN62, or by knock-down of P2X(7)Rs with small interfering RNAs. Therefore, extracellular ATP release from injured tissues may act as an accelerating factor in necrotic SN4741 dopaminergic cell death via P2X(7)Rs.X1149Nsciescopu

Mode Content Study of Propagating Waves Using Burn Patterns In the KSTAR 84-GHz ECH System

In order to transmit a wave efficiently in an electron cyclotron heating (ECH) system, it is important to suppress mode conversion loss caused by coupling in the matching optics unit and misalignment in the transmission line. To understand the cause of mode conversion loss, it is necessary to analyze the mode content in an oversized circular corrugated wave guide. For mode analysis of the propagating wave in the corrugated waveguide, several methods based on the phase-retrieval process and the iterative process are suggested. But, in the Korea Superconducting Tokamak Advanced Research 84-GHz ECH transmission line, a well-known method using burn patterns was used for better coupling of the output beam from the gyrotron onto the axis of the corrugated waveguide by adjusting a large ellipsoidal mirror in an L-shaped chamber, a so-called L-box. During the adjustment of the mirror in the L-box, evidence of the existence of higher modes other than HE11 was found. For the mode content study, the radiation intensity distribution was measured using thermal paper as a function of the distance along the waveguide at a high power level. The mode content of the wave was estimated by comparing the measured burn patterns and calculated patterns at different locations. This paper describes the results of mode content estimation using burn pattern images as a function of the mode mixture ratio.X111sciescopu