Human AK2 links intracellular bioenergetic redistribution to the fate of hematopoietic progenitors

AK2 is an adenylate phosphotransferase that localizes at the intermembrane spaces of the mitochondria, and its mutations cause a severe combined immunodeficiency with neutrophil maturation arrest named reticular dysgenesis (RD). Although the dysfunction of hematopoietic stem cells (HSCs) has been implicated, earlier developmental events that affect the fate of HSCs and/or hematopoietic progenitors have not been reported. Here, we used RD-patient-derived induced pluripotent stem cells (iPSCs) as a model of AK2-deficient human cells. Hematopoietic differentiation from RD-iPSCs was profoundly impaired. RD-iPSC-derived hemoangiogenic progenitor cells (HAPCs) showed decreased ATP distribution in the nucleus and altered global transcriptional profiles. Thus, AK2 has a stage-specific role in maintaining the ATP supply to the nucleus during hematopoietic differentiation, which affects the transcriptional profiles necessary for controlling the fate of multipotential HAPCs. Our data suggest that maintaining the appropriate energy level of each organelle by the intracellular redistribution of ATP is important for controlling the fate of progenitor cells

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

Current Views on the Roles of O-Glycosylation in Controlling Notch-Ligand Interactions

The 100th anniversary of Notch discovery in Drosophila has recently passed. The Notch is evolutionarily conserved from Drosophila to humans. The discovery of human-specific Notch genes has led to a better understanding of Notch signaling in development and diseases and will continue to stimulate further research in the future. Notch receptors are responsible for cell-to-cell signaling. They are activated by cell-surface ligands located on adjacent cells. Notch activation plays an important role in determining the fate of cells, and dysregulation of Notch signaling results in numerous human diseases. Notch receptors are primarily activated by ligand binding. Many studies in various fields including genetics, developmental biology, biochemistry, and structural biology conducted over the past two decades have revealed that the activation of the Notch receptor is regulated by unique glycan modifications. Such modifications include O-fucose, O-glucose, and O-N-acetylglucosamine (GlcNAc) on epidermal growth factor-like (EGF) repeats located consecutively in the extracellular domain of Notch receptors. Being fine-tuned by glycans is an important property of Notch receptors. In this review article, we summarize the latest findings on the regulation of Notch activation by glycosylation and discuss future challenges

Nonlinear resonance effects in a linear Paul trap

The effects of nonlinear resonances in a linear Paul trap have been investigated through systematic experiments and numerical simulations. The main causes of the nonlinearity that affects the stability of the ion motion are the use of circular (rather than hyperbolic) electrodes, their misalignments, and Coulomb interactions among the ions. A particle tracking code based on a two-dimensional model is employed to study the efficiency of plasma storage and to confirm the existence of nonlinear resonance stop bands. Experiments are performed with Ar+ plasmas that are eventually detected by a Faraday cup after a short storage. The obtained data are compared with numerical simulations in which the exact three-dimensional structure of the trap system has been incorporated. Several nonlinear stop bands have been experimentally identified inside the Mathieu stability region. It is demonstrated that the location of a resonance stop band moves due to the space-charge potential depending on the number of confined ions

Current Views on the Roles of <i>O</i>-Glycosylation in Controlling Notch-Ligand Interactions

The 100th anniversary of Notch discovery in Drosophila has recently passed. The Notch is evolutionarily conserved from Drosophila to humans. The discovery of human-specific Notch genes has led to a better understanding of Notch signaling in development and diseases and will continue to stimulate further research in the future. Notch receptors are responsible for cell-to-cell signaling. They are activated by cell-surface ligands located on adjacent cells. Notch activation plays an important role in determining the fate of cells, and dysregulation of Notch signaling results in numerous human diseases. Notch receptors are primarily activated by ligand binding. Many studies in various fields including genetics, developmental biology, biochemistry, and structural biology conducted over the past two decades have revealed that the activation of the Notch receptor is regulated by unique glycan modifications. Such modifications include O-fucose, O-glucose, and O-N-acetylglucosamine (GlcNAc) on epidermal growth factor-like (EGF) repeats located consecutively in the extracellular domain of Notch receptors. Being fine-tuned by glycans is an important property of Notch receptors. In this review article, we summarize the latest findings on the regulation of Notch activation by glycosylation and discuss future challenges

Properties of non-neutral electron plasmas confined with a magnetic mirror field

A low energy non-neutral electron plasma was confined with a magnetic mirror field and an electrostatic potential to investigate the basic confinement properties of a simple magnetic mirror trap. The mirror ratio of the magnetic field was increased up to 5. As expected the confinement time became longer as a function of the mirror ratio. The axially integrated radial density profiles in equilibrium were measured and compared with a theoretical model. The axial electrostatic oscillations of a confined electron plasma were also observed

Ultrafast time-resolved electron diffraction revealing the nonthermal dynamics of near-UV photoexcitation-induced amorphization in Ge2Sb2Te5

Because of their robust switching capability, chalcogenide glass materials have been used for a wide range of applications, including optical storages devices. These phase transitions are achieved by laser irradiation via thermal processes. Recent studies have suggested the potential of nonthermal phase transitions in the chalcogenide glass material Ge(2)Sb(2)Te(5) triggered by ultrashort optical pulses; however, a detailed understanding of the amorphization and damage mechanisms governed by nonthermal processes is still lacking. Here we performed ultrafast time-resolved electron diffraction and single-shot optical pump-probe measurements followed by femtosecond near-ultraviolet pulse irradiation to study the structural dynamics of polycrystalline Ge(2)Sb(2)Te(5). The experimental results present a nonthermal crystal-to-amorphous phase transition of Ge(2)Sb(2)Te(5) initiated by the displacements of Ge atoms. Above the fluence threshold, we found that the permanent amorphization caused by multi-displacement effects is accompanied by a partial hexagonal crystallization

Nitrogen Vacancy Center Created by Anisotropic and Hydrostatic High-Pressure-High-Temperature Treatment after Electron Irradiation

Nitrogen vacancy (NV) center is composed of a substitutional nitrogen and a vacancy on adjacent lattice sites in diamond. An electron spin of NV center can be detected and manipulated at room temperature, and spin state are utilized for quantum sensors for measuring small physical quantities. In order to improve the sensitivity of quantum sensors, it is important to create an NV center at a high concentration with controlled orientation. An electron beam which enables to introduce vacancies in nitrogen rich diamond substrate is useful to create dense NV centers. The highest NV concentration of 45 ppm has been achieved by combination of the electron beam irradiation with high temperature annealing in vacuum condition. However, orientation of NV centers created by the electron beam is always random. On the other hand, chemical vapor deposition (CVD) technique has realized the orientation of NV centers. A disadvantage of CVD technique is less NV center concentration compared with electron beam technique. In 2014, ab initio theoretical calculation showed that the orientation of NV centers can be controlled by high temperature annealing in the presence of strain. In this study, the anisotropic high-pressure-high-temperature (HPHT) treatment was applied to introduce the strain during high temperature annealing.The 2nd International Forum on Quantum Metrology and Sensing (IFQMS