Thermal design of superconducting cryogenic rotor: Solutions to conduction cooling challenges

This paper describes the design and testing of the first cryogenic rotor based on conductively cooled superconducting stacked tape pseudo bulks used in a rotating machine with various magnetisation methods. The rotor design demanded a number of unusual features and constraints that required novel, innovative solutions that may be applicable in other designs. The aim of this work is not to create a complete design manual, rather, to suggest some ideas that could be useful to others who are looking to solve similar problems. The outline of the proposed design is followed by a detailed description of the key systems and their interactions. Several innovative design characteristics are discussed, including calculation of liquid cryogenic cooling. Finally, experimental thermal results indicate that the design calculations are reliable and provide reaffirmation of the overall success of the design

Role of activating transcription factor 4 in the hepatic response to amino acid depletion by asparaginase

The anti-leukemic agent asparaginase activates the integrated stress response (ISR) kinase GCN2 and inhibits signaling via mechanistic target of rapamycin complex 1 (mTORC1). The study objective was to investigate the protective role of activating transcription factor 4 (ATF4) in controlling the hepatic transcriptome and mediating GCN2-mTORC1 signaling during asparaginase. We compared global gene expression patterns in livers from wildtype, Gcn2 -/-, and Atf4 -/- mice treated with asparaginase or excipient and further explored selected responses in livers from Atf4 +/- mice. Here, we show that ATF4 controls a hepatic gene expression profile that overlaps with GCN2 but is not required for downregulation of mTORC1 during asparaginase. Ingenuity pathway analysis indicates GCN2 independently influences inflammation-mediated hepatic processes whereas ATF4 uniquely associates with cholesterol metabolism and endoplasmic reticulum (ER) stress. Livers from Atf4 -/- or Atf4 +/- mice displayed an amplification of the amino acid response and ER stress response transcriptional signatures. In contrast, reduction in hepatic mTORC1 signaling was retained in Atf4 -/- mice treated with asparaginase

IDEFIX: a versatile performance-portable Godunov code for astrophysical flows

Exascale super-computers now becoming available rely on hybrid energy-efficient architectures that involve an accelerator such as Graphics Processing Units (GPU). Leveraging the computational power of these machines often means a significant rewrite of the numerical tools each time a new architecture becomes available. To address these issues, we present Idefix, a new code for astrophysical flows that relies on the Kokkos meta-programming library to guarantee performance portability on a wide variety of architectures while keeping the code as simple as possible for the user. Idefix is based on a Godunov finite-volume method that solves the non-relativistic HD and MHD equations on various grid geometries. Idefix includes a wide choice of solvers and several additional modules (constrained transport, orbital advection, non-ideal MHD) allowing users to address complex astrophysical problems. Idefix has been successfully tested on Intel and AMD CPUs (up to 131 072 CPU cores on Irene-Rome at TGCC) as well as NVidia and AMD GPUs (up to 1024 GPUs on Adastra at CINES). Idefix achieves more than 1e8 cell/s in MHD on a single NVidia V100 GPU and 3e11 cell/s on 256 Adastra nodes (1024 GPUs) with 95% parallelization efficiency (compared to a single node). For the same problem, Idefix is up to 6 times more energy efficient on GPUs compared to Intel Cascade Lake CPUs. Idefix is now a mature exascale-ready open-source code that can be used on a large variety of astrophysical and fluid dynamics applications.Comment: 18 pages, 18 figures, 3 tables, accepted for publication in Astronomy & Astrophysic

Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver

Disturbances in protein folding and membrane compositions in the endoplasmic reticulum (ER) elicit the unfolded protein response (UPR). Each of three UPR sensory proteins-PERK (PEK/EIF2AK3), IRE1, and ATF6-is activated by ER stress. PERK phosphorylation of eIF2 represses global protein synthesis, lowering influx of nascent polypeptides into the stressed ER, coincident with preferential translation of ATF4 (CREB2). In cultured cells, ATF4 induces transcriptional expression of genes directed by the PERK arm of the UPR, including genes involved in amino acid metabolism, resistance to oxidative stress, and the proapoptotic transcription factor CHOP (GADD153/DDIT3). In this study, we characterize whole-body and tissue-specific ATF4-knockout mice and show in liver exposed to ER stress that ATF4 is not required for CHOP expression, but instead ATF6 is a primary inducer. RNA-Seq analysis indicates that ATF4 is responsible for a small portion of the PERK-dependent UPR genes and reveals a requirement for expression of ATF4 for expression of genes involved in oxidative stress response basally and cholesterol metabolism both basally and under stress. Consistent with this pattern of gene expression, loss of ATF4 resulted in enhanced oxidative damage, and increased free cholesterol in liver under stress accompanied by lowered cholesterol in sera

GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment

The antileukemic agent asparaginase triggers the amino acid response (AAR) in the liver by activating the eukaryotic initiation factor 2 (eIF2) kinase general control nonderepressible 2 (GCN2). To explore the mechanism by which AAR induction is necessary to mitigate hepatic lipid accumulation and prevent liver dysfunction during continued asparaginase treatment, wild-type and Gcn2 null mice were injected once daily with asparaginase or phosphate buffered saline for up to 14 days. Asparaginase induced mRNA expression of multiple AAR genes and greatly increased circulating concentrations of the metabolic hormone fibroblast growth factor 21 (FGF21) independent of food intake. Loss of Gcn2 precluded mRNA expression and circulating levels of FGF21 and blocked mRNA expression of multiple genes regulating lipid synthesis and metabolism including Fas, Ppara, Pparg, Acadm, and Scd1 in both liver and white adipose tissue. Furthermore, rates of triglyceride export and protein expression of apolipoproteinB-100 were significantly reduced in the livers of Gcn2 null mice treated with asparaginase, providing a mechanistic basis for the increase in hepatic lipid content. Loss of AAR-regulated antioxidant defenses in Gcn2 null livers was signified by reduced Gpx1 gene expression alongside increased lipid peroxidation. Substantial reductions in antithrombin III hepatic expression and activity in the blood of asparaginase-treated Gcn2 null mice indicated liver dysfunction. These results suggest that the ability of the liver to adapt to prolonged asparaginase treatment is influenced by GCN2-directed regulation of FGF21 and oxidative defenses, which, when lost, corresponds with maladaptive effects on lipid metabolism and hemostasis