Deficiency of the RIβ subunit of protein kinase A causes body tremor and impaired fear conditioning memory in rats

The RIβ subunit of cAMP-dependent protein kinase (PKA), encoded by Prkar1b, is a neuronal isoform of the type I regulatory subunit of PKA. Mice lacking the RIβ subunit exhibit normal long-term potentiation (LTP) in the Schaffer collateral pathway of the hippocampus and normal behavior in the open-field and fear conditioning tests. Here, we combined genetic, electrophysiological, and behavioral approaches to demonstrate that the RIβ subunit was involved in body tremor, LTP in the Schaffer collateral pathway, and fear conditioning memory in rats. Genetic analysis of WTC-furue, a mutant strain with spontaneous tremors, revealed a deletion in the Prkar1b gene of the WTC-furue genome. Prkar1b-deficient rats created by the CRISPR/Cas9 system exhibited body tremor. Hippocampal slices from mutant rats showed deficient LTP in the Schaffer collateral–CA1 synapse. Mutant rats also exhibited decreased freezing time following contextual and cued fear conditioning, as well as increased exploratory behavior in the open field. These findings indicate the roles of the RIβ subunit in tremor pathogenesis and contextual and cued fear memory, and suggest that the hippocampal and amygdala roles of this subunit differ between mice and rats and that rats are therefore beneficial for exploring RIβ function

Fabrication of high-concentration Cu-doped deuterated targets for fast ignition experiments

In high-energy-density physics, including inertial fusion energy using high-power lasers, doping tracer atoms and deuteration of target materials play an important role in diagnosis. For example, a low-concentration Cu dopant acts as an x-ray source for electron temperature detection while a deuterium dopant acts as a neutron source for fusion reaction detection. However, the simultaneous achievement of Cu doping, a deuterated polymer, mechanical toughness and chemical robustness during the fabrication process is not so simple. In this study, we report the successful fabrication of a Cu-doped deuterated target. The obtained samples were characterized by inductively coupled plasma optical emission spectrometry, differential scanning calorimetry and Fourier transform infrared spectroscopy. Simultaneous measurements of Cu K-shell x-ray emission and beam fusion neutrons were demonstrated using a petawatt laser at Osaka University.Ikeda T., Kaneyasu Y., Hosokawa H., et al. Fabrication of high-concentration Cu-doped deuterated targets for fast ignition experiments. Nuclear Fusion 63, 016010 (2023); https://doi.org/10.1088/1741-4326/aca2ba

Demonstration of a spherical plasma mirror for the counter-propagating kilojoule-class petawatt LFEX laser system

A counter-propagating laser-beam platform using a spherical plasma mirror was developed for the kilojoule-class petawatt LFEX laser. The temporal and spatial overlaps of the incoming and redirected beams were measured with an optical interferometer and an x-ray pinhole camera. The plasma mirror performance was evaluated by measuring fast electrons, ions, and neutrons generated in the counter-propagating laser interaction with a Cu-doped deuterated film on both sides. The reflectivity and peak intensity were estimated as ∼50% and ∼5 × 1018 W/cm2, respectively. The platform could enable studies of counter-streaming charged particles in high-energy-density plasmas for fundamental and inertial confinement fusion research.Kojima S., Abe Y., Miura E., et al. Demonstration of a spherical plasma mirror for the counter-propagating kilojoule-class petawatt LFEX laser system. Optics Express 30, 43491 (2022); https://doi.org/10.1364/oe.475945

Direct fast heating efficiency of a counter-imploded core plasma employing a laser for fast ignition experiments (LFEX)

Fast heating efficiency when a pre-imploded core is directly heated with an ultraintense laser (heating laser) was investigated. \u27Direct heating\u27 means that a heating laser hits a pre-imploded core without applying either a laser guiding cone or an external field. The efficiency, η, is defined as the increase in the internal core energy divided by the energy of the heating laser. Six beams (output of 1.6 kJ) from the GEKKO XII (GXII) green laser system at the Institute of Laser Engineering (ILE), Osaka University were applied to implode a spherical deuterated polystyrene (CD) shell target to form a dense core. The DD-reacted protons and the core x-ray emissions showed a core density of 2.8 ± 0.7 g cm−3, or 2.6 times the solid density. Furthermore, DD-reacted thermal neutrons were utilized to estimate the core temperature between 600 and 750 eV. Thereafter, the core was directly heated by a laser for fast-ignition experiments (LFEX, an extremely energetic ultrashort pulse laser) at ILE with its axis lying along or perpendicular to the GXII bundle axis, respectively. The former and latter laser configurations were termed \u27axial\u27 and \u27transverse modes\u27, respectively. The η was estimated from three independent methods: (1) the core x-ray emission, (2) the thermal neutron yield, and (3) the runaway hot electron spectra. For the axial mode, 0.8%< η <2.1% at low power (low LFEX energy) and 0.4%< η <2.5% at high power (high LFEX energy). For the transverse mode, 2.6%< η <7% at low power and 1.5%< η <7.7% at high power. Their efficiencies were compared with that in the uniform implosion mode using 12 GXII beams, 6% < η <12%, which appeared near to the η for the transverse mode, except that the error bar is very large

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target